Nina Wettschureck and Stefan Offermanns - Physiological Reviews

Mammalian G Proteins and Their Cell Type Specific Functions 

NINA WETTSCHURECK AND STEFAN OFFERMANNS 

Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany 

Physiol Rev 85: 1159–1204, 2005; 

doi:10.1152/physrev.00003.2005. 

I. Introduction 1160 

A. Basic principles of G protein-mediated signaling 1160 

B. G protein �-subunits and ��-complexes 1163 

II. Cardiovascular System 1167 

A. Autonomic control of heart function 1167 

B. Myocardial hypertrophy 1168 

C. Smooth muscle tone 1169 

D. Platelet activation 1171 

III. Endocrine System and Metabolism 1173 

A. Hypothalamo-pituitary system 1173 

B. Pancreatic �-cells 1174 

C. Thyroid gland/parathyroid gland 1175 

D. Regulation of carbohydrate and lipid metabolism 1175 

IV. Immune System 1177 

A. Leukocyte migration/homing 1177 

B. Immune cell effector functions 1178 

V. Nervous System 1179 

A. Inhibitory modulation of synaptic transmission 1179 

B. Modulation of synaptic transmission by the Gq/G11-mediated signaling pathway 

C. Roles of Gz and Golf in the nervous system 

VI. Sensory Systems 

1179 

1180 

1180 

A. Visual system 1181 

B. Olfactory/pheromone system 1181 

C. Gustatory system 1182 

VII. Development 1182 

A. G13-mediated signaling in embryonic angiogenesis 

B. Gq/G11-mediated signaling during embryonic myocardial growth 

C. Neural crest development 

1183 

1183 

1183 

VIII. Cell Growth and Transformation 1184 

A. Constitutively active mutants of G�q/G�11 family members 

B. The oncogenic potential of G�s C. Gi-mediated cell transformation 

D. Cellular growth induced by G�12/G�13 IX. Concluding Remarks 

1184 

1184 

1185 

1185 

1185 

Wettschureck, Nina, and Stefan Offermanns. Mammalian G Proteins and Their Cell Type Specific Functions. 

Physiol Rev 85: 1159–1204, 2005; doi:10.1152/physrev.00003.2005.—Heterotrimeric G proteins are key players in 

transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector 

molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins 

represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed 

by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as 

perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of 

cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of 

heterotrimeric G proteins in defined cells and tissues are described. 

www.prv.org 0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society 

1159

1160 NINA WETTSCHURECK AND STEFAN OFFERMANNS 

I. INTRODUCTION 

All cells possess transmembrane signaling systems 

that allow them to receive information from extracellular 

stimuli like hormones, neurotransmitters, or sensory 

stimuli. This fundamental process allows cells to communicate 

with each other. All transmembrane signaling systems 

share two basic elements, a receptor which is able to 

recognize an extracellular stimulus as well as an effector 

which is controlled by the receptor and which can generate 

an intracellular signal. Many transmembrane signaling 

systems like receptor tyrosine kinases incorporate these 

two elements in one molecule. In contrast, the G proteinmediated 

signaling system is relatively complex consisting 

of a receptor, a heterotrimeric G protein, and an 

effector. This modular design of the G protein-mediated 

signaling system allows convergence and divergence at 

the interfaces of receptor and G protein as well as of G 

protein and effector. In addition, each component, the 

receptor, the G protein as well as the effector can be 

regulated independently by additional proteins, soluble 

mediators, or on the transcriptional level. The relatively 

complex organization of the G protein-mediated transmembrane 

signaling system provides the basis for a huge 

variety of transmembrane signaling pathways that are 

tailored to serve particular functions in distinct cell types. 

It is probably this versatility of the G protein-mediated 

signaling system that has made it by far the most often 

employed transmembrane signaling mechanism. In this 

review we summarize some of the biological roles of G 

protein-mediated signaling processes in the mammalian 

organism which are based on their cell type-specific function. 

Although we have tried to cover a wide variety of 

cellular systems and functions, the plethora of available 

data forced us to restrict this review. Particular emphasis 

is placed on cellular G protein functions that have been 

studied in primary cells or in the context of the whole 

organism using genetic approaches. 

A. Basic Principles 

of G Protein-Mediated Signaling 

More than 1,000 G protein-coupled receptors (GPCRs) 

are encoded in mammalian genomes. While most of them 

code for sensory receptors like taste or olfactory receptors, 

�400–500 of them recognize nonsensory ligands like 

hormones, neurotransmitters, or paracrine factors (53, 

185, 519, 534, 649). For more than 200 GPCRs, the physiological 

ligands are known (Table 1). GPCRs for which 

no endogenous ligand has been found are “orphan” 

GPCRs (376, 389, 688). 

Upon activation of a receptor by, e.g., its endogenous 

ligand, coupling of the activated receptor to the heterotrimeric 

G protein is facilitated. Multiple site-directed mu- 

Physiol Rev • VOL 85 • OCTOBER 2005 • www.prv.org 

tagenesis experiments have been performed on G proteincoupled 

receptors, and they have revealed various cytoplasmic 

domains of the receptors that are involved in the 

specific interaction between the receptors and the G protein. 

However, despite the determination of the structure 

of rhodopsin at atomic resolution (504), it is still not clear 

how specificity of the receptor-G protein interaction is 

achieved and how a ligand-induced conformational 

change in the receptor molecule results in G protein 

activation (177, 212, 213, 565, 674). 

The heterotrimeric G protein consists of an �-subunit 

that binds and hydrolyzes GTP as well as of a �- and a 

�-subunit that form an undissociable complex (233, 255, 

475). Several subtypes of �-, �-, and �-subunits have been 

described (Table 2). To dynamically couple activated receptors 

to effectors, the heterotrimeric G protein undergoes 

an activation-inactivation cycle (Fig. 1). In the basal 

state, the ��-complex and the GDP-bound �-subunit are 

associated, and the heterotrimer can be recognized by an 

appropriate activated receptor. Coupling of the activated 

receptor to the heterotrimer promotes the exchange of 

GDP for GTP on the G protein �-subunit. The GTP-bound 

�-subunit dissociates from the activated receptor as well 

as from the ��-complex, and both the �-subunit and the 

��-complex are now free to modulate the activity of a 

variety of effectors like ion channels or enzymes. Signaling 

is terminated by the hydrolysis of GTP by the GTPase 

activity, which is inherent to the G protein �-subunit. The 

resulting GDP-bound �-subunit reassociates with the ��complex 

to enter a new cycle if activated receptors are 

present. For recent excellent reviews on basic structural 

and functional aspects of G proteins, see References 49, 

83, 361, and 526. 

While the kinetics of G protein activation through 

GPCRs has been well described for quite a while, only 

recently has the regulation of the deactivation process 

been understood in more detail. Based on the observation 

that the GTPase activity of isolated G proteins is much 

lower than that observed under physiological conditions, 

the existence of mechanisms that accelerate the GTPase 

activity had been postulated. Various effectors have indeed 

been found to enhance GTPase activity of the G 

protein �-subunit, thereby contributing to the deactivation 

and allowing for rapid modulation of G protein-mediated 

signaling (23, 45, 348, 571). More recently, a family 

of proteins called “regulators of G protein signaling” (RGS 

proteins) has been identified, which is also able to increase 

the GTPase activity of G protein �-subunits (272, 

481, 550). There are �30 RGS proteins currently known, 

which have selectivities for G protein �-subfamilies. The 

physiological role of RGS proteins is currently under investigation. 

Besides their role in the modulation of G 

protein-mediated signaling kinetics, they also influence 

the specificity of the signaling process and in some cases 

may have effector functions.

TABLE 1. Physiological ligands of G protein-coupled receptors 

Endogenous Ligand(s) Receptor 

Coupling to G Protein 

Subclass(es) Reference Nos. 

Amino acids, dicarboxylic acids 

Glutamate 

�-Aminobutyric acid (GABA) 

�-Ketoglutarate 

Succinate 

L-Arginine, L-lysine 

Biogenic Amines 

mGluR1,5 

mGluR2,3,4,6,7,8 

GABAB1 (binding), GABAB2 (signaling) 

GPR99 

GPR91 

GPRC6A 

Gq/11 Gi/o Gi/o Gq/11 Gq/11, Gi/o Gq/11 ? 

117 

117 

64 

248 

248 

673 

Acetylcholine 

Epinephrine, norepinephrine 

Dopamine 

Histamine 

Melatonin 

Serotonin 

Trace amines 

Ions 

M1,M3,M5 M2,M4 �1A,�1B,�1D �2A,�2B,�2C �1,�2,�3 D1,D5 D2,D3,D4 H1 H2 H3,H4 MT1,MT2,MT3 5-HT1A/B/D/E/F 5-HT2A/B/C 5-HT4,5-HT6,5-HT7 5-HT5A/B TA1, TA2 

Gq/11 Gi/o Gq/11 Gi/o Gs Gs Gi/o Gq/11 Gs Gi/o Gi/o Gi/o Gq/11 Gs Gi/o, Gs Gs 675 

675 

252 

252 

399 

487 

487 

262 

262 

262 

151 

281 

281 

281, 466, 467 

281 

57, 80 

Ca 2� 

CaSR G q/11, G i/o 218 

H � 

Nucleotides/nucleosides 

SPC1, G2A 

GPR4, TDAG-8 

Gq/11, G12/13 Gs 403, 465 

403, 658 

Adenosine 

ADP 

ADP/ATP 

ATP 

UDP 

UDP-glucose 

UTP/ATP 

Lipids 

A1,A3 A2A, A2B P2Y12, P2Y13 P2Y1 P2Y11 P2Y6 P2Y14 P2Y2, P2Y4 Gi/o Gs Gi/o Gq/11 Gq/11, Gs Gq/11 Gi/o Gq/11 184 

184 

273, 422 

183 

183 

183 

1 

183 

Anandamide, 2-arachidonoyl glycerol CB 1,CB 2 G i/o 280 

11-Cis-retinal (covalently bound for 

light-dependent receptor activation; 

see below) 

CELLULAR FUNCTIONS OF G PROTEINS 1161 

Rhodopsin G t-r 717 

Opsins (green, blue, red) G t-c 471 

Melanopsin G q/11 ? 436, 505, 530 

Fatty acids (C 2–C 5) GPR41, GPR43 G i/o, G q/11 72 

(C 12–C 20) GPR40 G q/11 70 

(C 14–C 22) GPR120 G q/11 265 

5-Oxo-ETE TG1019, GPR170 G i/o 69 

Leukotrinene B 4 (LTB 4) BLT G i/o 68 

LTC 4, LTD 4 CysLT1, CysLT2 G q/11 68 

LXA 4 FPRL1 (ALXR) G i/o 68 

Lysophosphatidic acid (LPA) LPA 1/2/3 (Edg2/4/7) G i,G q/11, G 12/13 110 

Platelet-activating factor (PAF) PAF G q/11 528 

Prostacyclin (PGI 2) IP G s 238, 470 

Prostaglandin D 2 (PGD 2) DP G s 238, 470 

CRTH 2 G i 238, 470 

Prostaglandin F 2� (PGF) FP G q/11 238, 470 

Prostaglandin E 2 (PGE 2) EP 1 G q/11 238, 470 

EP 2,EP 4 G s 238, 470 

EP 3 G s,G q/11, G i 238, 470 

Spingosine-1-phosphate (S1P) S1P 1/2/3/4/5 (Edg1/5/3/6/8) G i,G q/11, G 12/13 293 

Spingosylphosphorylcholine (SPC) SPC 1 (OGR1), SPC 2 (GPR4) G i 706, 735 

Thromboxane A 2 (TxA 2) TP G q/11, G 12/13 238, 470 

Peptides/proteins 

Adrenocorticotrophin (ACTH) MC 2 G s 682 

Adrenomedullin AM 1 (CL�RAMP2), AM 2 (CL�RAMP3) G s 525 

Physiol Rev • VOL 85 • OCTOBER 2005 • www.prv.org


TABLE 1—Continued 

Endogenous Ligand(s) Receptor 



Amylin 

Angiotensin II 

Apelin 

Bradykinin 

Calcitonin 

Calcitonin gene-related peptide (CGRP) 

CC chemokines 

CXC chemokines 

CX3C chemokines 

Cholecyctokinin (CCK-8) 

Complement C3a/C5a 

Corticitropin-releasing factor (CRF), 

urocortin 

AMY1 (CT�RAMP1), AMY2 (CT�RAMP2), AMY3 (CT�RAMP3) 

AT1 AT2 APJ 

B1,B2 CT 

CGRP1 (CL�RAMP1) 

CCR1,2,3,4,5,6,7,8,9,10 

CXCR1,2,3,4,5,6 

XCL1, XCL2, CX3L1 

CCK1, CCK2 C3a, C5a 

CRF1, CRF2 Gs Gq/11, G12/13, Gi/o ? 

Gi/o Gq/11 Gs,Gq/11 Gs,Gq/11 Gi/o Gi/o Gi/o Gq/11, Gs Gi/o Gs 525 

134 

627 

378 

525 

525 

466, 467 

466, 467 

466, 467 

582 

208 

239 

Endothelin-1, -2, -3 

Follicle-stimulating hormone (FSH) 

Formyl-Met-Leu-Phe (fMLP) 

Galanin, galanin-like peptide 

Gastric inhibitory peptide 

Gastrin 

Gastrin-releasing peptide (GRP), 

bombesin 

ETA (ET-1, ET-2), ETB (ET-1, -2, -3) 

FSH 

FPR 

GAL1, GAL3 

GAL2 

GIP 

CCK2 BB2 

Gq/11, G12/13, Gs Gs Gi/o Gi/o Gi/o, Gq/11, G12/13 Gs Gq/11 Gq/11 131 

648 

373 

657 

657 

332, 431 

582 

36 

Ghrelin 

Glucagon 

Glucagon-like peptide 

Gonadotropin-releasing hormone 

Growth hormone-releasing hormone 

Kisspeptins, metastin 

Luteinizing hormone, 

choriogonadotropin 

GHS-R 

Glucagon 

GLP1, GLP2 

GnRH 

GHRH 

GPR54 

LSH 

Gq/11 Gs Gs Gq/11 Gs Gq/11 Gs,Gi 342 

431 

431 

445 

206, 431 

137, 575 

648 

Melanin-concentrating hormone 

Melanocortins 

Motilin 

Neurokinin-A/-B (NK-A/-B) 

Neuromedin-B, bombesin 

Neuromedin U 

Neuropeptide FF & AF 

Neuropeptide W-23, W-30 

Neuropeptide Y (NPY) etc. 

Neurotensin 

Opioids (�-endorphin, Met/Leuenkephalin, 

dynorphin A, nociceptin/ 

orphanin FQ) 

MCH1 

MCH2 

MC1,MC3,MC4,MC5 GPR38 

NK2 (NK-A), NK3 (NK-B) 

BB1 

NMU1 (FM-3), NMU2 (FM-4) 

NPFF1, NPFF2 

GRP7, GPR8 

Y1,Y2,Y4,Y5,Y6 NTS1, NTS2 

�, �, �, ORL1 

Gi/o? Gq/11 Gs Gq/11 Gq/11 Gq/11 Gq/11 Gi/o Gi/o Gi/o Gq/11 Gi/o 63 

682 

173 

513 

496 

67 

54 

580 

440 

654 

370 

Orexin A/B 

Oxytocin 

Parathyroid hormone (related peptide) 

Prokineticin-1,2 

Prolactin-releasing peptide 

Relaxin, insulin-like 3 

Secretin 

Somatostatin 

Substance P (SP) 

Thyrotropin (TSH) 

Thyrotropin-releasing hormone (TRH) 

Urotensin II 

Vasoactive intestinal polypeptide (VIP), 

PACAP 

OX1, OX2 

OT 

PTH/PTHrP 

PK-R1, PK-R2 

PrRP (GPR10) 

LGR7, LGR8 

Secretin 

SST1, SST2, SST3, SST4, SST5 NK1 TSH 

TRH-1, TRH-2 

UT-II (GPR14) 

VPAC1, VPAC2, PAC1 Gs,Gq/11 Gq/11, Gi/o Gs,Gq/11 Gq/11 Gq/11 Gs Gs Gi/o Gq/11 Gs,Gq/11, Gi,G12/13 Gq/11 Gq/11 Gs 442 

256 

203 

591 

613 

35 

431 

511 

513 

648 

614 

150 

651 

Vasopressin 

Proteases (the new NH2-terminal domain 

produced by proteolytic cleavage 

serves as a tethered ligand) 

V1a, V1b V2 Gq/11 Gs 256 

256 

Thrombin and others 

Trypsin and others 

PAR-1, PAR-3, PAR-4 

PAR-2 

Gq/11, G12/13, Gi/o Gq/11 271 

271 


TABLE 1—Continued 

Sensory Stimuli Receptor 

The interaction of G proteins with the inner side of 

the plasma membrane is facilitated by lipid modifications 

of both the �-subunit as well as of the �-subunit of the 

��-complex (97, 448, 589, 728). Recent data provide evidence 

that heterotrimeric G proteins of the G i family are 

also involved in receptor-independent processes (52, 

413), which appear to be critically involved in the positioning 

of the mitotic spindle and the attachment of microtubules 

to the cell cortex (234). These processes also 

involve a group of proteins that carry a so-called GoLoco 

motif which functions as a guanine nucleotide dissociation 

inhibitor (684). 

B. G Protein �-Subunits and ��-Complexes 

The functional versatility of the G protein-mediated 

signaling system is based on its modular architecture and 

on the fact that there are numerous subtypes of G proteins. 

The �-subunits that define the basic properties of a 

heterotrimeric G protein can be divided into four families, 

G� s,G� i/G� o,G� q/G� 11, and G� 12/G� 13 (Table 2). Each 

family consists of various members that often show very 

specific expression patterns. Members of one family are 

structurally similar and often share some of their functional 

properties. The ��-complex of mammalian G proteins 

is assembled from a repertoire of 5 G protein �-subunits 

and 12 �-subunits (Table 2). While �1- to �4-subunits 

form a tight complex with �-subunits which can only be 

separated under denaturing conditions, the �5-subunit 

interaction with �-subunits is comparably weak (347, 

543). The �5-subunit is an exception in that it can also be 

found in a complex with a subgroup of RGS proteins 

(689). The ��-complex was initially regarded as a more 




Light 

�500 nm (max. absorption) 




�425–480 nm (max. absorption) 

Taste 

Rhodopsin (11-cis-retinal) 

Blue-opsin (11-cis-retinal) 

Green-opsin (11-cis-retinal) 

Red-opsin (11-cis-retinal) 

Melanopsin (11-cis-retinal) 

Gt-r Gt-c Gt-c Gt-c Gq/11? 717 

471 

471 

471 

436, 505, 530 

Umami 

Sweet 

Bitter 

T1R1 � T1R3 

mGluR4 

T1R2 � T1R3 

T2 receptor group (many; �25 in 

human, �36 in mouse) 

Ggust? Gi/o Ggust? Ggust? 457, 477, 730 

95 

457, 477, 730 

94, 457, 463 

Odorants many (�350 in human, �1,000 in 

mouse) 

Golf 77, 457 

Pheromones V1 group (few in human, �150 in 

Gi2 ? 428, 457 

mouse) 

V2 group (none in human, �150 in 

mouse) 

In the reference column, reviews are cited whenever possible to limit the number of references. 


G o ? 428, 457 

passive partner of the G protein �-subunit. However, it 

has become clear that ��-complexes freed from the G 

protein �-subunit can regulate various effectors (112). 

These ��-mediated signaling events include the regulation 

of ion channels (488), of particular isoforms of adenylyl 

cyclase and phospholipase C (169, 615), as well as 

of phosphoinositide-3-kinase isoforms (641). With a few 

exceptions, the ability of different ��-combinations to 

regulate effector functions does not dramatically differ 

(112). 

Most receptors are able to activate more than one G 

protein subtype. The activation of a G protein-coupled 

receptor therefore usually results in the activation of 

several signal transduction cascades via G protein �-subunits 

as well as through the freed ��-complex. The pattern 

of G proteins activated by a given receptor determines 

the cellular and biological response, and activated 

receptors that lead to functionally similar or identical 

cellular effects usually activate the same G protein subtypes. 

The G protein receptor interaction in general does 

not occur in an absolutely specific or in a completely 

promiscuous manner. Some receptors appear to interact 

only with certain G protein subforms, and in some cellular 

systems, the compositions of defined G protein-mediated 

signaling pathways can be very specific. However, there 

are some characteristic patterns of receptor-G protein 

coupling that have been described for the majority of 

receptors (Fig. 2). 

The G proteins of the G i/G o family are widely expressed 

and especially the �-subunits of G i1, G i2 and G i3 

have been shown to mediate receptor-dependent inhibition 

of various types of adenylyl cyclases (615). Because 

the expression levels of G i and G o are relatively


TABLE 2. Heterotrimeric G proteins 

Name Gene Expression Effector(s) 

�-Subunits 

G�s class 

G�s GNAS Ubiquitous AC (all types) 1 

G�sXL (GNASXL) Neuroendocrine AC 1 

G�olf GNAL Olfactory epithelium, brain AC 1 

G�i/o class 

G�i1 GNAI1 Widely distributed AC (types I,III,V,VI,VIII,IX) 2 (directly regulated) 

G�i2 GNAI2 Ubiquitous 

various other effectots are regulated via G�� 

G�i3 G�o G�z G�gust G�t-r G�t-c G�q/11 class 

G�q G�11 G�14 G�15/16 G�12/13 class 

G�12 G�13 �-Subunits 

GNAI3 

GNAO 

GNAZ 

GNAT3 

GNAT1 

GNAT2 

GNAQ 

GNA11 

GNA14 

GNA16 (Gna15) 

GNA12 

GNA13 

Widely distributed 

Neuronal, neuroendocrine 

Neuronal, platelets 

Taste cells, brush cells 

Retinal rods, taste cells 

Retinal cones 

Ubiquitous 

Almost ubiquitous 

Kidney, lung, spleen 

Hematopoietic cells 

Ubiquitous 

Ubiquitous 

released from activated Gi1-3 (see below) 

VDCC2, GIRK1 (via G��; see below) 

AC (e.g., V,VI) 2 (directly regulated); Rap1GAP 

PDE 1?; other effectors via G��? 

PDE 6 (�-subunit rod) 1 

PDE 6 (�-subunit cone) 1 

PLC-�1-4 1 

PLC-�1-4 1 

PLC-�1-4 1 

PLC-�1-4 1 

PDZ-RhoGEF/LARG, Btk, Gap1m, cadherin 

p115RhoGEF, PDZ-RhoGEF/LARG, radixin 

�1 GNB1 Widely, retinal rods AC type I 2 AC types II,IV,VII 1 PLC-� 

�2 GNB2 Widely distributed 

(�3��2��1) 1 GIRK1–4 (Kir3.1–3.4) 1 receptor 

�3 GNB3 Widely, retinal cones 

kinases (GRK 2 and 3) 1 PI-3-K, �, � 1 T type 

�4 �5 �-Subunits 

GNB4 

GNB5 

Widely distributed 

Mainly brain 

VDCC (Cav3.2) 2 (G�2�2) N-,P/Q-,R-type VDCC 

(Cav2.1–2.3) 2 

�1, �rod GNGT1 Retinal rods, brain, 

�14, �cone GNGT2 Retinal cones, brain 

�2, �6 GNG2 Widely 

�3 GNG3 Brain, blood 

�4 GNG4 Brain and other tissues 

�5 GNG5 Widely 


�8, �9 GNG8 Olfactory/vomeronasal epithelium 




�13 GNG13 Brain, taste buds 

AC, adenylyl cyclase; PDE, phosphodiesterase; PLC, phospholipase C; GIRK, G protein-regulated inward rectifier potassium channel; VDCC, 

voltage-dependent Ca 2� channel; PI-3-K, phosphatidylinositol 3-kinase; GRK, G protein-regulated kinase; RhoGEF, Rho guanine nucleotide exchange 

factor. 

high, their receptor-dependent activation results in the 

release of relatively high amounts of ��-complexes. 

Activation of G i/G o is therefore believed to be the major 

coupling mechanism that results in the activation of 

��-mediated signaling processes (112, 543). The function 

of members of the G i/G o family has often been 

studied using a toxin from Clostridium botulinum 

(pertussis toxin; PTX) which is able to ADP-ribosylate 

most of the members of the G� i/G� o family close to 

their COOH termini. COOH-terminally ADP-ribosylated 

G� i/G� o is unable to interact with the receptor. Thus 

PTX treatment results in the uncoupling of the receptor 

and G i/G o. The structural similarity between the 3 G� i 

subforms suggests that they may have partially overlapping 

functions. In contrast to other G proteins, the 

effects of G o, which is particularly abundant in the 


nervous system, appears to be primarily mediated by its 

��-complex. Whether G� o can regulate effectors directly 

is currently not clear. A less widely expressed 

member of the G� i/G� o family is G� z (438), which in 

contrast to G i and G o is not a substrate for PTX. G� z is 

expressed in various tissues including the nervous system 

and platelets. It shares some functional similarities 

with G i-type G proteins but has recently been shown to 

interact specifically with various other proteins including 

Rap1GAP and certain RGS proteins (438). Several 

�-subunits like gustducin and transducins belong to the 

G� i/G� o family and are involved in specific sensory 

functions (24, 126). 

The G q/G 11 family of G proteins couples receptors to 

�-isoforms of phospholipase C (169, 538). The �-subunits 

of G q and G 11 are almost ubiquitously expressed while the

FIG. 1. Functional cycle of G protein activity. The complex of a 

7-transmembrane domain receptor and an agonist (Ag) promotes the 

release of GDP from the �-subunit of the heterotrimeric G protein 

resulting in the formation of GTP-bound G�. GTP-G� and G�� dissociate 

and are able to modulate effector functions. The spontaneous hydrolysis 

of GTP to GDP can be accelerated by various effectors as well as by 

regulators of G protein signaling (RGS) proteins. GDP-bound G� then 

reassociates with G��. 

other members of this family like G� 14 and G� 15/16 (G� 15 

being the murine, G� 16 the human ortholog) show a rather 

restricted expression pattern. Receptors that are able to 

couple to the G q/G 11 family do not appear to discriminate 

between G q and G 11 (490, 660, 696, 705). Similarly, there is 

obviously no difference between the abilities of both G 

protein �-subunits to regulate phospholipase C �-isoforms. 

While G� q and G� 11 both are good activators of 

�1-, �3-, and �4-isoforms of phospholipase C (PLC), the 

PLC �2-isoform is a poor effector for both (538). The 

biological significance of the diversity among the G� q 

gene family is currently not clear. While the importance of 

G q and G 11 in various biological processes has been well 

established, the roles of G� 14 and G� 15/16, which show 

very specific expression patterns, are not clear. Mice carrying 

inactivating mutations of the G� 14 and G� 15 genes 

have no or very minor phenotypical changes (132; H. Jiang 

and M. I. Simon, personal communication). In contrast, 

mice lacking G� q or both G� q and G� 11 have multiple 

defects (489, 494, 495) (see below). 

The G proteins G 12 and G 13, which are often activated 

by receptors coupling to G q/G 11, constitute the G 12/G 13 

family and are expressed ubiquitously (139, 607). The 

analysis of cellular signaling processes regulated through 

G 12 and G 13 has been difficult since specific inhibitors of 

these G proteins are not available. In addition, G 12/G 13- 



coupled receptors usually also activate other G proteins. 

Most information on the cellular functions regulated by 

G 12/G 13 therefore came from indirect experiments employing 

constitutively active mutants of G� 12/G� 13. These 

studies showed that G 12/G 13 can induce a variety of signaling 

pathways leading to the activation of various 

downstream effectors including phospholipase A 2, 

Na � /H � exchanger, or c-jun NH 2-terminal kinase (139, 

193, 276, 523, 607). Another important cellular function of 

G 12/G 13 is their ability to regulate the formation of actomyosin-based 

structures and to modulate their contractility 

by increasing the activity of the small GTPase RhoA 

(79). Activation of RhoA by G� 12 and G� 13 is mediated by 

a subgroup of guanine nucleotide exchange factors 

(GEFs) for Rho which include p115-RhoGEF, PDZ-Rho- 

GEF, and LARG (194, 236, 618). While the RhoGEF activity 

of PDZ-RhoGEF and LARG appears to be activated by 

both G� 12 and G� 13, p115-RhoGEF activity is stimulated 

only by G� 13. Recently, an interesting link between G 12/ 

G 13 and cadherin-mediated signaling was described, both 

G� 12 and G� 13 interact with the cytoplasmic domain of 

some type I and type II class cadherins, causing the 

release of �-catenin from cadherins (434, 435). Various 

other proteins including Bruton’s tyrosine kinase, the Ras 

GTPase-activating protein Gap1m, radixin, heat shock 

protein 90, AKAP110, protein phosphatase type 5, or 

Hax-1 have also been shown to interact with G� 12 and/or 

G� 13 (309, 359, 485, 532, 638, 709). 

The ubiquitously expressed G protein G s couples 

many receptors to adenylyl cyclase and mediates receptor-dependent 

adenylyl cyclase activation resulting in increases 

in the intracellular cAMP concentration. The 

�-subunit of G s,G� s, is encoded by GNAS, a complex 

imprinted gene that gives rise to several gene products 

due to the presence of various promoters and splice variants 

(Fig. 3). In addition to G� s, two transcripts encoding 

XL� s and Nesp55 are generated by promoters upstream of 

the G� s promoter. While the chromogranin-like protein 

Nesp55 is structurally and functionally not related to G� s, 

XL� s is structurally identical to G� s but has an extra long 

NH 2-terminal extension that is encoded by a specific first 

exon (329). In contrast to G� s,XL� s has a limited expression 

pattern being mainly expressed in the adrenal gland, 

heart, pancreatic islets, brain, and the pars intermedia of 

the pituitary (509). However, XL� s shares with G� s the 

ability to bind to ��-subunits and to mediate receptordependent 

stimulation of cAMP production (33, 339). Interestingly, 

the first exon of the Gnasxl gene encodes 

another protein termed ALEX (338), which is able to 

interact with the XL domain of XL� s and to inhibit its 

activity (188, 338). Interestingly, Nesp55 and XL� s are 

differentially imprinted. While the promoter of Nesp55 is 

DNA-methylated on the paternally inherited allele resulting 

in the expression only from the maternally inherited 

allele, the promoter driving XL� s expression is methyl-


FIG. 2. Typical patterns of receptor/G protein coupling. Although there are many exceptions, three basic patterns of receptor-G protein coupling 

have been found which critically define the cellular response after ligand-dependent receptor activation. � 2, � 2-adrenergic receptor; D 1–5, dopamine 

receptor subtypes 1 to 5; GIRK, G protein-regulated inward rectifier potassium channel; 5-HT 1,2, serotonin receptor subtypes 1 and 2; M 1–5, 

muscarinic acetylcholine receptor subtypes 1 to 5; mGluR1–7, metabotropic glutamate receptor subtypes 1 to 7; PLC-�, phospholipase C-�; PI-3-K, 

phosphoinositide-3-kinase; PIP 2, phosphatidylinositol 4,5-bisphosphate; IP 3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; 

Rho-GEF, Rho-guanine nucleotide exchange factor; TP, thromboxane A 2 receptor; IP, prostacyclin receptor. 

ated on the maternal allele, and XL� s is only expressed 

from the paternal allele (244, 245, 515). Several other 

transcripts like Nespas of which some are believed to be 


untranslated show ubiquitous expression and are derived 

from the paternal allele due to differentially methylated 

promoter regions (243, 294, 396, 619). In contrast, the 

FIG. 3. Model of the GNAS gene complex with 

some of its transcripts. Some of the transcripts generated 

from the maternal and paternal allele are 

shown on the top and bottom, respectively. Open 

boxes indicate noncoding sequences; closed boxes 

indicate coding sequences. Exon 3 of the GNAS gene 

(hatched box) is alternatively spliced out giving rise 

to long and short forms of G� s. Promoters active on 

the maternal and paternal allele are indicated by arrows. 

While Nesp is only expressed from the maternal 

allele, XL� s and Nespas are expressed from the paternal 

allele. The GNAS promoter is biallelically active; 

however, in a few tissues only the maternal allele 

is expressed (see text). Several other transcripts of 

the GNAS gene complex have been described; however, 

their function is unclear. Exon sequences are 

shown in black and white for coding and noncoding 

sequences, while transcripts are shown in gray and 

white for coding and noncoding sequences.

promoter driving the expression of G� s has been shown 

to be biallelically active and to lack differential methylation 

(85, 244, 245, 733). However, in a few tissues such as 

the renal proximal tubules, the thyroid, pituitary, and 

ovaries, the paternal G� s expression is silenced by an as 

yet undefined mechanism (209, 242, 394, 414, 723). 

II. CARDIOVASCULAR SYSTEM 

A. Autonomic Control of Heart Function 

Cardiac regulation by the sympathetic system is mediated 

by �-adrenergic receptors that are coupled primarily 

to G s (Fig. 4). cAMP produced in response to G s 

activation directly modulates the gating of hyperpolarization-activated, 

cyclic nucleotide-gated channels and activates 

protein kinase A (PKA) which in turn phosphorylates 

several proteins involved in excitation-contraction 

coupling including L-type Ca 2� channels, phospholamban, 

or troponin I (44). These cellular changes are believed 

to underlie the well-known effects of sympathetic 

cardiac activation including positive chronotropic, 

dromotropic, lusitropic, and inotropic effects (545). 

Transgenic overexpression of the short form of G� s 

(G� s-S) in the murine heart had no effect on the basal 

cardiac function but resulted in an enhanced efficacy of 

�-adrenoceptor G s signaling, and chronotropic and inotropic 

responses to catecholamines were increased (299). 

Once G� s-overexpressing mice become older, they develop 

clinical and pathological signs of cardiomyopathy 

(300). These pathological processes are accompanied by a 

lack of normal heart rate variability as well as of protective 

desensitization mechanisms (635, 650). The development 

of cardiomyopathy after prolonged overexpression 

of G� s is in line with the current concept of the pathophysiological 

mechanisms underlying the development of 

chronic heart failure. The insufficient cardiac output char- 


acteristic for heart failure typically goes along with an 

increased sympathetic tone resulting in chronic catecholamine 

stimulation of cardiomyocytes, which is believed to 

be deleterious (71). Although the � 1-adrenoceptor is the 

predominant subtype expressed in cardiomyocytes, also 

� 2-adrenoceptors are expressed in the heart (545). Interestingly, 

there is increasing evidence that � 1- and � 2adrenoceptors 

play different roles in catecholamine-induced 

cardiomyopathy. Mice overexpressing human � 2adrenoceptors 

have only slightly altered cardiac function 

and appear to have normal life expectancy (259, 260, 443, 

544) while mice overexpressing � 1-adrenoceptors develop 

severe hypertrophy and die of heart failure (162). The � 1and 

� 2-adrenoceptors also differ with regard to their signal 

transduction. While � 1-adrenergic receptors are G s 

coupled, � 2-adrenoceptors are also able to couple to G itype 

G proteins (700, 701) (Fig. 4). The additional activation 

of G i via � 2-adrenergic receptors may explain the 

observed differences in signaling induced via � 1- and 

� 2-adrenergic receptors (116, 125, 232, 405, 725, 736). This 

led to the hypothesis that � 2-adrenoceptor stimulation 

exerts some sort of protection against cardiac hypertrophy 

and failure, especially under conditions of chronic 

activation of the �-adrenergic system and that this is due 

to signaling via G i. The well-documented upregulation of 

G i in human heart failure (174, 482) may be a mechanism 

to counteract deleterious G s-mediated signaling. The potential 

cardioprotective role of G i is also supported by 

studies in mice. While the overexpression of � 2-adrenergic 

receptors in normal cardiomyocytes is well tolerated, 

mice which lack in addition the major G i �-subunit, G� i2, 

die within a few days after birth (180). Mice that overexpress 

� 2-adrenoceptors in cardiomyocytes and which 

carry only one intact G� i2 gene allele develop more pronounced 

cardiac hypertrophy and earlier heart failure 

compared with � 2-adrenoceptor transgenic animals with 

normal G� i2 levels. 

FIG. 4. Role of heterotrimeric G proteins in mediating autonomic control of heart function by the sympathetic and parasympathetic system. 

� 1/� 2, � 1- and � 2-adrenergic receptor; M 2, muscarinic receptor; I f, pacemaker channel; GIRK, G protein-regulated inward rectifier potassium channel; 

VDCC, voltage-dependent calcium channel; PKA, protein kinase A. 



The muscarinic acetylcholine (M 2) receptor that is 

coupled to G i/G o G proteins mediates the parasympathetic 

regulation of the heart (Fig. 4). The negative chronotropic 

and dromotropic effects of the parasympathetic 

system are believed to result from the G i-mediated inhibition 

of adenylyl cyclase, resulting in an inhibition of the 

cAMP production as well as by the activation of G proteinregulated 

inward rectifier potassium channels (GIRK) by 

��-subunits released from activated G i/G o (601). The 

atrial GIRK consists of Kir3.1 and Kir3.4 subunits. Mice 

lacking either of the two channel subunits have normal 

basal heart rates but show reduced vagal and adenosinemediated 

slowing of heart rate and markedly reduced 

heart rate variability, which is thought to be determined 

by the vagal tone (47, 680). The involvement of G�� 

complexes in regulation of GIRK channels has been well 

established using electrophysiological and biochemical 

approaches (349, 398, 679). Mice in which the amount of 

functional G�� protein was reduced by more than 50% in 

cardiomyocytes also show an impaired parasympathetic 

heart rate control (207). The central role of G� i in inhibitory 

regulation of heart rate and atrioventricular conductance 

has led to attempts to treat cardiac arrhythmias by 

atrioventricular nodal gene transfer of G� i2 in a model of 

persistent atrial fibrillation in swine (146). While wild-type 

G� i2 did not change basal heart rate, a constitutively 

active mutant of G� i2 resulted in a significant decrease in 

heart rate. When tested for their effects in a model for 

tachycardia-induced cardiomyopathy, the condition was 

significantly improved by wild-type G� i2 and even more 

by constitutively active G� i2 (37). In addition to the stimulatory 

regulation of potassium channels, muscarinic regulation 

of heart function also involves inhibition of voltage-dependent 

L-type Ca 2� channels via an unknown 

mechanism. In mice lacking the �-subunit of G o, inhibitory 

muscarinic regulation of cardiac L-type Ca 2� channels 

was abrogated, although G� o represents only a minor 

fraction of all G proteins in the heart (639). Interestingly, 

mice which lack the �-subunit of G i2 (G� i2) also show a 

severely affected inhibitory regulation of L-type Ca 2� 

channels via muscarinic M 2 receptors (101, 468). This 

suggests that both G proteins, G o and G i2, are involved in 

the regulation of cardiac L-type Ca 2� channels. 

B. Myocardial Hypertrophy 

Myocardial hypertrophy is the chronic adaptive response 

of the heart to injury or increased hemodynamic 

load. It is characterized by increased cardiomyocyte size 

and protein content, as well as altered gene expression, 

recapitulating an embryonic phenotype (109, 301). Such 

pathological myocardial hypertrophy was shown to be 

associated with increased cardiac mortality (191, 285, 

535), raising the question whether prevention of patho- 


logical hypertrophy is beneficial or not (191). Several 

mechanosensitive mechanisms involving stretch-activated 

ion channels, integrins or Z-disc proteins were suggested 

to mediate myocardial hypertrophy in response to 

pressure overload (191, 285, 535). In addition, GPCR agonists 

like norepinephrine/phenylephrine, angiotensin II, 

or endothelin-1 were shown to induce a hypertrophic 

phenotype in cultured rat embryonic cardiomyocytes (4, 

341, 560, 581). These ligands are known to activate G q/ 

G 11-coupled receptors, such as the � 1-adrenergic receptor, 

the angiotensin AT 1 receptor, or the endothelin ET A 

receptor (362, 561, 592). Activation of G� q by Pasteurella 

multocida toxin (559) or expression of wild-type G� q (5, 

362) induces the hypertrophic phenotype in cultured cardiomyocytes, 

while inhibition of G q/G 11 by the RGS domain 

of GRK2 inhibited agonist-induced hypertrophy 

(423). In vivo, cardiac-restricted expression of wild-type 

(128) or constitutively active G� q (437) results in cardiac 

hypertrophy. In addition, in vivo overexpression of typically 

G q/G 11-coupled receptors (444, 474) or their downstream 

effectors (65, 454, 656) induces hypertrophy. Conversely, 

in vivo inhibition of G q/G 11 by overexpression of 

RGS4, a GTPase-activating G protein for G q/G 11 and G i/G o 

(547), or by overexpression of the COOH terminus of G� q 

(10) results in a reduced hypertrophic response, and cardiomyocyte-specific 

inactivation of the genes encoding 

G� q/G� 11 completely abrogates the hypertrophic response 

elicited by pressure overload (677). Interestingly, 

an impaired hypertrophic response due to inhibition of 

G q/G 11-mediated signaling does not negatively influence 

long-term cardiac function (166), suggesting that hypertrophy 

in response to pressure overload is not necessarily 

required to maintain cardiac function. In addition to pressure 

overload-induced myocardial hypertrophy, the G q/ 

G 11-mediated signaling pathway was also implicated in 

the pathogenesis of diabetic cardiomyopathy. G� q levels 

and PKC activity were shown to be enhanced in the 

streptozotocin-induced diabetic rat heart (714), and heart 

specific overexpression of RGS4 protected mice against 

different models of diabetic cardiomyopathy. In contrast, 

heart-specific expression of a RGS-resistant G� q caused 

sensitization towards diabetic cardiomyopathy (235). The 

downstream signaling processes in G q/G 11-mediated hypertrophy 

are complex and not fully understood (Fig. 5). 

Intracellular Ca 2� mobilization in response to activation 

of G q/G 11-coupled receptors promotes Ca 2� /calmodulin 

(CaM)-dependent activation of calcineurin, which in turn 

mediates dephosphorylation and nuclear translocation of 

transcription factors of the NFAT (nuclear factor of activated 

T cells) family. Although activation of the calcineurin/NFAT 

signaling pathway is clearly sufficient to 

induce myocardial hypertrophy, it is not completely clear 

whether inhibition of this signaling pathway prevents hypertrophy 

(for review, see Refs. 190, 191). In addition, a 

variety of other effectors have been implicated in myo-

FIG. 5.G q/G 11 family G proteins are centrally involved in myocardial 

hypertrophy. G protein-coupled receptors like the � 1-adrenergic 

receptor (� 1), the angiotensin AT 1 receptor, or the endothelin ET A 

receptor act through G q/G 11 to induce hypertrophy via activation of 

downstream effectors including the calcineurin/NFAT pathway, PKC 

isoforms, MAP kinases, the PI-3-kinase/Akt/GSK-3 pathway or small 

GTPases. CaM, calmodulin; DAG, diacylglycerol; IP 3, inositol 1,4,5trisphosphate; 

MAPK, mitogen-activated protein kinases; NFAT, nuclear 

factor of activated T cells; PI-3-K, phosphoinositide-3-kinase; PIP 2, phosphatidylinositol 

4,5-bisphosphate; PKC, protein kinase C; PLC-�, phospholipase 

C-�. 

cardial hypertrophy, such as protein kinase C (PKC) isoforms, 

mitogen-activated protein (MAP) kinases, the 

phosphatidylinositol (PI) 3-kinase/Akt/GSK-3 pathway or 

small GTPases (for review, see Refs. 148, 191, 285, 535). 

GPCRs known to mediate myocardial hypertrophy 

can also activate G 12/G 13 family G proteins, resulting in 

the activation of RhoA (215, 257). RhoA was suggested to 

be involved in the hypertrophic responses to phenylephrine, 

endothelin, chronic hypertension, or overexpression 

of G� q (128, 264, 278, 360, 562, 567). Expression of inhibitory 

COOH-terminal peptides of G� 12 and G� 13, as well 

as expression of the G 12/G 13 specific RGS domain of 

p115RhoGEF, inhibited phenylephrine-mediated JNK activation 

in neonatal cardiomyocytes (423). In addition, 

overexpression of a constitutively active mutant of G� 13 

induced a hypertrophic response in neonatal cardiomyocytes, 

with increased expression of the hypertrophy-asso- 


ciated embryonic gene program (179). However, no in 

vivo data on the role of G 12/G 13 in myocardial hypertrophy 

are available. 

C. Smooth Muscle Tone 


Smooth muscle tone is controlled by the phosphorylation 

state of the regulatory light chain (MLC 20) of myosin 

II (for review, see Refs. 269, 593, 594). MLC 20 is 

phosphorylated by the Ca 2� /CaM-dependent myosin light 

chain kinase (MLCK), leading to enhanced velocity and 

force of actomyosin cross-bridging. Dephosphorylation of 

MLC 20 is mediated by myosin phosphatase, an enzyme 

that is negatively regulated by the Rho/Rho-kinase pathway. 

Thus increased contractility can be achieved 

through Ca 2� -mediated MLCK activation and through 

Rho-dependent inhibition of MLC 20 dephosphorylation. A 

variety of transmitters and hormones regulate smooth 

muscle tone through GPCRs (Fig. 6). Typical vasoconstrictor 

receptors, such as the angiotensin AT 1 receptor, 

the endothelin ET A receptor, or the � 1-adrenergic receptor, 

act on G q/G 11-coupled receptors (159, 215, 724) to 

enhance intracellular Ca 2� concentration, leading to 

MLCK activation. Increased intracellular Ca 2� levels are 

not only due to IP 3-mediated Ca 2� release from the sarcoplasmic 

reticulum, but also to Ca 2� influx through cation 

channels or voltage-gated Ca 2� channels (for review, 

see Refs. 269, 593). In addition, many G q/G 11-coupled 

receptors have been shown to activate RhoA, thereby 

contributing to Ca 2� -independent smooth muscle contraction 

(593, 594). Smooth muscle specific overexpression 

of a COOH-terminal G� q peptide, which is believed to 

inhibit the receptor/G protein interaction, ameliorates hypertension 

induced by long-term treatment with phenylephrine, 

serotonin, or angiotensin II (331). Mice lacking 

RGS2, a GTPase activating G protein which accelerates 

the inactivation of G q/G 11, suffer from hypertension (261). 

Interestingly, it was recently shown that the nitric oxide/ 

cGMP cascade, which constitutes the main relaxant pathway 

in smooth muscle cells, negatively regulates G q/G 11 

signaling by cGMP kinase-mediated phosphorylation and 

activation of RGS2 (625). However, in addition to this 

peripheral vascular mechanism, an increased sympathetic 

tone might contribute to elevated arterial blood pressure 

in RGS2-deficient mice (227). 

In vitro, most G q/G 11-coupled vasoconstrictor receptors 

also activate G 12/G 13 family G proteins, like the receptors 

for endothelin-1, vasopressin, angiotensin II (215, 

257), thrombin (411), or thromboxane A 2 (491, 492). Constitutively 

active forms of G� 12 and G� 13 induced a pronounced, 

RhoA-dependent contraction in cultured vascular 

smooth muscle cells, and receptor-mediated contractions 

were strongly inhibited by dominant negative forms 

of G� 12 and G� 13 (215). These data suggest that also the


G 12/G 13-mediated signaling pathway is involved in the 

regulation of smooth muscle tone, most likely by modulating 

the activity of myosin phosphatase via Rho/Rhokinase. 

In accordance with this, inhibition of Rho-kinase 

was shown to normalize blood pressure in humans and 

experimental animals (426, 636). The relative contribution 

of G q/11/Ca 2� -mediated and G 12/13/Rho/Rho-kinase-mediated 

signaling to regulation of vascular smooth muscle 

tone is not clear. However, data obtained in visceral 

smooth muscle suggested that G q/G 11 conveys a fast, transient 

response, while G 12/G 13 mediates a sustained, tonic 

contraction (257). 

Vascular smooth muscle relaxation is mediated by a 

variety of mechanisms, one of them being the activation 

of G s-coupled receptors like the adenosine A 2 receptors, 

� 2-adrenergic receptors, or prostaglandin receptor subtypes 

IP, DP, and EP 2. How the subsequent increase in 

cAMP levels reduces smooth muscle tone is not understood. 

In vitro data suggest that the relaxant effect is 

partially due to a PKA-mediated MLCK phosphorylation, 

which decreases the enzyme’s affinity for the Ca 2� /CaM 

complex, but the physiological relevance of this signaling 

pathway is unclear. Possible other substrates for PKA are 

heat shock protein 20, RhoA, or myosin phosphatase (for 

review, see Ref. 269). cAMP has also been suggested to 

cross-activate cGMP kinase I in vascular or airway 

smooth muscle (32, 390), but this hypothesis has been 


FIG. 6. Heterotrimeric G proteins involved 

in the regulation of smooth muscle tone. G q/ 

G 11-coupled receptors increase the intracellular 

Ca 2� concentration, leading to Ca 2� /calmodulin 

(CaM)-dependent MLCK activation 

and MLC 20 phosphorylation. Especially G 12/ 

G 13-coupled receptors mediate RhoA activation, 

thereby contributing to Ca 2� -independent 

smooth muscle contraction. Relaxation is induced 

by activation of G s-coupled receptors, 

but the mechanisms underlying cAMP-mediated 

relaxation are not clear. G i-mediated signaling 

might contribute to contraction by inhibiting 

G s-mediated relaxation. cGKI, cGMP-dependent 

protein kinase I; DAG, diacylglycerol; 

IP 3, inositol 1,4,5-trisphosphate; MLC 20, regulatory 

chain of myosin II; MLCK, myosin lightchain 

kinase; MPP, myosin phosphatase; PIP 2, 

phosphatidylinositol 4,5-bisphosphate; PKA, 

cAMP-dependent kinase; PLC-�, phospholipase 

C-�; RhoGEF, Rho specific guanine nucleotide 

exchange factor; ROCK, Rho kinase; TRP, transient 

receptor potential channel. 

questioned by the finding that vessels from cGKI-deficient 

mice relax normally in response to cAMP (518). In addition, 

cAMP-independent mechanisms of G s-mediated relaxation 

involving large-conductance, Ca 2� -activated K � 

(MaxiK, BK) channels have been proposed (624). 

The role of G i-mediated signaling in vascular smooth 

muscle tone seems to differ between different vessel 

types. An inhibitory effect of PTX on norepinephrineinduced 

contractility was reported in rat tail artery (516, 

600) but was absent in aorta (517). High blood pressure in 

spontaneously hypertensive rats is preceded by increased 

expression of G i proteins (18, 19), and PTX treatment 

delayed the onset of hypertension (387), suggesting that 

decreased cAMP levels play a role in the pathogenesis of 

this model of hypertension. Enhanced signaling via a 

PTX-sensitive G protein was reported in immortalized B 

lymphoblasts from patients with essential hypertension 

(520), and this was attributed to a C825T polymorphism in 

the gene coding for G� 3, a constituent of the G i heterotrimer 

(586). The C825T polymorphism was suggested to 

be associated with an increased risk of hypertension, 

obesity, and arteriosclerosis in some (for review, see Ref. 

585) but not in all studies (283, 616, 617). However, the 

significance of genetic association studies in general remains 

controversial (20, 199, 291). 

Very similar to vascular smooth muscle, also airway 

smooth muscle tone is mainly regulated by G q/G 11 family

G proteins, which mediate bronchoconstriction, and G s 

family G proteins, which mediate bronchorelaxation. Acetylcholine 

released from postganglionic parasympathetic 

nerves controls resting tone mainly via the G q/G 11-coupled 

M 3 receptor subtype (90), but also other G q/G 11coupled 

receptors are expressed in airway smooth muscles, 

like the H 1 histamine receptor (133, 222), the leukotriene 

CysLT1 receptor (314), the B 2 bradykinin receptor 

(421, 630), the ET B endothelin receptor (216, 241, 441), 

and others. Airway hyperreactivity in the A/J mouse strain 

was suggested to be due to enhanced agonist affinity and 

increased G protein coupling efficiency of the M 3 muscarinic 

receptor (205), and G q protein was shown to be 

upregulated in antigen-induced airway hyperresponsive 

rats (106). Mice lacking the �-subunit of G q showed impaired 

metacholine-induced airway responses and lacked 

the typical increase in metacholine sensitivity after allergen 

sensitization and reexposition (55). Not much is 

known about the role of G� 12 and G� 13 in airway smooth 

muscle tone regulation. The fact that repetitive antigen 

challenge significantly increases the expression of these 

proteins in airway smooth muscle suggests a role in allergic 

asthma (105, 108), but direct evidence for an involvement 

of G 12/G 13 is still lacking. G s-coupled receptors play 

an important role in the relaxation of contracted airway 

smooth muscle, most prominently the � 2-adrenergic receptor, 

but also the prostaglandin E 2 receptor EP 2 (512) 

or the prostacyclin IP receptor (41) (for review, see Ref. 

628). The G i family of G proteins contributes to the regulation 

of airway smooth muscle contractility mainly by 

inhibiting the relaxant effects of G s. The inhibitory effect 

of PTX on acetylcholine-induced bronchoconstriction is 

negligible in normal rats, but significant in rats suffering 

from antigen-induced airway hyperresponsiveness (107). 

In these mice, G� i3 protein is upregulated in bronchial 

smooth muscle cells, suggesting that the relative contri- 


bution of G i-mediated constriction is increased in antigenchallenged 

airway smooth muscle (107). 

D. Platelet Activation 


Platelets are small cell fragments that circulate in the 

blood and adhere at places of vascular injury to the vessel 

wall where they become activated resulting in the formation 

of a platelet plug that is responsible for primary 

hemostasis. Platelets can also become activated under 

pathological conditions, e.g., on ruptured atherosclerotic 

plaques leading to arterial thrombosis. Platelet adhesion 

and activation is initiated by their interaction with adhesive 

macromolecules like collagen and von Willebrand 

factor (vWF) at the subendothelial surface (303, 554). 

While collagen is able to induce firm adhesion of platelets 

to the subendothelium (666), the recruitment of additional 

platelets to the growing platelet plaque requires the 

local accumulation of diffusible mediators that are produced 

or released once platelet adhesion has been initiated, 

and some level of activation through platelet adhesion 

receptors has occurred (3). These mediators include 

ADP/ATP and thromboxane A 2 (TxA 2), which are secreted 

or released from activated platelets as well as 

thrombin, which is produced on the surface of activated 

platelets. These platelet stimuli have in common their 

action through G protein-coupled receptors. While ADP 

induces the activation of G q and G i via P2Y 1 and P2Y 12 

receptors (197, 354), the activated TxA 2 receptor (TP) 

couples to G q and G 12/G 13 (337, 492) (Fig. 7). G proteincoupled 

protease-activated receptors (PARs) that are activated 

by thrombin are functionally coupled to G q,G 12/ 

G 13, and in some cases to G i (121). In response to these 

secondary mediators of platelet activation, platelets immediately 

undergo a shape change reaction during which 

they become spherical and extrude pseudopodia-like 

FIG. 7. Role of heterotrimeric G proteins 

in mediating platelet activation by 

soluble mediators like ADP, thromboxane 

A 2 (TxA 2), thrombin, and epinephrine. 

Major roles are played by the G proteins 

G q,G 13, and G i which couple receptors 

to the indicated effector molecules. 

The subsequent signaling processes eventually 

lead to platelet responses like 

shape change, degranulation, and aggregation 

(for details, see text). TP, TxA 2 

receptor; PAR, protease-activated receptor; 

P2Y 1/P2Y 12, purinergic receptors; 

� 2A, � 2A-adrenergic receptor; RhoGEF, 

Rho guanine nucleotide exchange factor; 

PLC-�2/3, phospholipase C-�2/3; PI-3-K, 

phosphoinositide-3-kinase; PIP 2, phosphatidylinositol 

4,5-bisphosphate; IP 3, 

inositol 1,4,5-trisphosphate; DAG, diacylglycerol; 

PKC, protein kinase C; PIP 3, 

phosphatidylinositol 3,4,5-trisphosphate.


structures. In addition, the glycoprotein IIb/IIIa (integrin 

�IIb�3) undergoes a conformational change resulting in 

binding of fibrinogen/vWF and subsequent platelet aggregation. 

Finally, the formation and release of TxA 2, thrombin, 

and ADP is further stimulated. Thus secondary mediators 

increase through G protein-coupled receptors 

their own formation resulting in an amplification of their 

effects, and eventually all G protein-mediated signaling 

pathways induced via these receptors become activated. 

The multiple positive feedback mechanisms operating 

during platelet activation have obscured the exact analysis 

of the roles individual G protein-mediated signaling 

pathways play during the platelet activation process. 

Progress has recently been made using genetic mouse 

models in understanding the role of individual G proteinmediated 

signaling pathways during platelet activation. 

The requirement of G q-mediated signaling for agonist-induced 

platelet activation has been demonstrated by 

the phenotype of G� q-deficient platelets, which fail to 

aggregate and to secrete in response to thrombin, ADP, 

and TxA 2 due to a lack of agonist-induced phospholipase 

C activation. This dramatic phenotype found in G� q-deficient 

platelets is due to the fact that platelets lack G� 11 

(313), which is in most other cells coexpressed with G� q 

and can compensate G� q deficiency. Mice lacking G� q 

have increased bleeding times and are protected against 

collagen/epinephrine-induced thromboembolism (494). 

Although G q-mediated signaling appears to be absolutely 

required for platelet activation, there is clear evidence 

that also G i type G proteins need to be activated to induce 

full activation of integrin �IIb�3. In mice lacking the 

�-subunit of G i2, the response of ADP that acts through 

the G i-coupled P2Y 12 receptor is reduced (304). However, 

also the effects of mediators like thrombin and TxA 2, 

which primarily signal through G q and G 12/G 13 were found 

to be inhibited in platelets lacking G� i2 (304, 712). This 

supports the view that platelet activation by thrombin and 

thromboxane A 2 requires in part the action of secondary 

mediators like ADP, which are released after activation of 

G q-mediated signaling pathways through TxA 2 and thrombin 

receptors. An important role of the G i-mediated signaling 

pathway in platelet activation is also suggested by 

studies in platelets lacking the G q-coupled P2Y 1 receptor 

or after pharmacological blockade of P2Y 1 (170, 251, 310, 

379, 568). These platelets do not aggregate in response to 

low and intermediate concentrations of ADP unless G qmediated 

signaling is induced via activation of another 

receptor. Similarly, platelets lacking P2Y 12 or in which 

P2Y 12 was pharmacologically blocked did not aggregate in 

response to ADP unless the G i-mediated pathway was 

activated via a different receptor (181, 568). Thus there is 

clear evidence that G q and G i synergize to induce platelet 

activation. It is currently not clear how G i contributes to 

integrin �IIb�3 activation in platelets, but a decrease in 

cAMP levels is unlikely to be involved (129, 529, 569, 712). 


Another member of the G i family of heterotrimeric G 

proteins, G z, has been implicated in platelet activation 

induced by epinephrine acting on � 2-adrenergic receptors. 

In contrast to ADP, TxA 2, and thrombin, epinephrine 

is alone not able to fully activate mouse platelets. However, 

it is able to potentiate the effect of other platelet 

stimuli. In G� z-deficient platelets, the inhibitory effect of 

epinephrine on adenylyl cyclase and epinephrine-potentiating 

effects were strongly impaired while the effects of 

other platelet activators appear to be unaffected (713). 

Despite the central role of G q in platelet activation, it 

was recently demonstrated that induction of G i- and G 12/ 

G 13-mediated signaling pathways is sufficient to induce 

integrin �IIb�3 activation (149, 483). Interestingly, in 

G� 13-deficient platelets, but not in G� 12-deficient platelets, 

the potency of various stimuli including TxA 2, thrombin, 

and collagen to induce platelet shape change and 

aggregation is markedly reduced (455). These defects are 

accompanied by a defect in the activation of RhoA and a 

delayed phosphorylation of the myosin light chain as well 

as by an inability to form stable platelet thrombi under 

high sheer stress conditions (455). In addition, mice carrying 

platelets that lack G� 13 have an increased bleeding 

time and are protected against the formation of arterial 

thrombi induced in a carotid artery thrombosis model 

(455). These data indicate that in addition to G q and G i 

also G 13 is crucially involved in the signaling processes 

mediating platelet activation via G protein-coupled receptors 

both in hemostasis and thrombosis. These findings 

also indicated that G 13-mediated signaling is not only 

involved in the response of platelets to relatively low 

stimulus concentrations that induce platelet shape 

change but is also required for normal responsiveness of 

platelets at higher stimulus concentrations. A reduced 

potency of platelet activators in the absence of G 13-mediated 

signaling becomes in particular limiting under high 

flow conditions that lead to a rapid clearance of soluble 

stimuli from the site of platelet activation and formation 

of mediators. In addition, the defective activation of 

RhoA-mediated signaling in the absence of G 13 appears to 

contribute to the observed defect in the stabilization of 

platelet aggregates under high sheer stress ex vivo as well 

as in vivo. In fact, RhoA-mediated signaling has been 

suggested to be required for platelet aggregation under 

high sheer conditions as well as for the irreversible aggregation 

of platelets in suspension (450, 570). 

These studies have clearly shown that three G proteins 

are major mediators of platelet activation via G 

protein-coupled receptors: G q, G i2, and G 13. However, 

even in the absence of either G q,G i2, orG 13 some platelet 

activation can still be induced, while in the absence of 

both G� q and G� 13, platelets are unresponsive to thrombin, 

TxA 2, or ADP. This indicates that the activation of 

G i-mediated signaling alone is not sufficient to induce any 

platelet activation (456). The optimal activation of plate-

lets under physiological and pathological conditions obviously 

requires the parallel signaling through several heterotrimeric 

G proteins. 

III. ENDOCRINE SYSTEM AND METABOLISM 

The endocrine system consists of a variety of glands 

and other structures that produce, store, and secrete hormones 

directly into the systemic circulation, thereby controlling 

electrolyte and water homeostasis, metabolism, 

growth, reproduction, etc. GPCRs contribute to endocrine 

functions in a twofold way: 1) by mediating hormonal end 

organ effects and 2) by controlling hormone secretion 

itself. Hormone secretion, as well as secretion from neuronal 

or exocrine cells, typically involves elevation of 

cytosolic Ca 2� and/or cAMP (for review, see Refs. 160, 

738). In most secretory cells, Ca 2� influx through voltageoperated 

Ca 2� channels is the dominant mode of regulation, 

like in adrenal chromaffin cells (160), while in other 

cells, such as anterior pituitary gonadotropes, Ca 2� mobilization 

from internal stores is the critical step (633). In 

yet another endocrine cell, such as lactotroph cells, both 

increased intracellular Ca 2� levels and cAMP production 

contribute to secretion (130, 186, 620). Accordingly, with 

rare exceptions, activation of G s and/or G q/G 11 family G 

proteins enhances secretion regardless of the endocrine 

cell type involved. 

A. Hypothalamo-Pituitary System 

Hormone release from the anterior pituitary is tightly 

controlled by hypothalamic releasing hormones and release 

inhibiting factors, all of which act through GPCRs. 

The receptors for corticotropin-releasing hormone (263) 

and growth hormone-releasing hormone (GHRH) (588) 

primarily act through G s, while receptors for gonadotropin-releasing 

hormone (445), thyrotropin-releasing 

hormone (211, 720), and the many prolactin-releasing factors 

(186) mainly act through G q/G 11 family G proteins, 

and only partly through G s. In addition to their secretagogue 

effects, hypothalamic releasing hormones regulate 

hormone synthesis and cell proliferation (81, 430, 531, 

583, 587, 647). Anterior pituitary secretion and proliferation 

is not only stimulated by the classical hypothalamic 

releasing hormones, but also by a variety of other factors, 

such as the gastrointestinal peptide hormone ghrelin, 

which enhances growth hormone (GH) secretion via 

the predominantly G q/G 11-coupled growth hormone 

secretagogue receptor GHS-R (343, 588), or members of 

the pituitary adenylate cyclase-activating polypeptide 

(PACAP)/glucagon superfamily, which exert secretagogue 

effects on a variety of pituitary cell types via their 

G s-coupled receptors (579). The in vivo relevance of G s 

family G proteins in anterior pituitary function was stud- 



ied in mice and in patients with inactivating or activating 

G s mutants. Somatotroph-specific overexpression of cholera 

toxin, which irreversibly activates G s by ADP ribosylation, 

caused somatotroph hyperplasia, increased GH 

levels and gigantism in mice (82). In humans, activating 

mutations of GNAS can be found in �40% of GH producing 

pituitary tumors (363, 406), as well as in 10% of 

nonfunctioning pituitary adenomas (406, 632, 685). These 

activating mutations of GNAS encode substitutions of 

either Arg-201 or Gln-227, two residues that are critical for 

the GTPase reaction (187, 223, 363, 406). In GH-secreting 

tumors, the mutation is almost always in the maternal 

allele, presumably because G� s is mainly expressed from 

the maternal allele (“paternally imprinted”) in pituitary 

cells (242). Activating GNAS mutations were also, though 

rarely, found in corticotroph (541, 686), but not in thyrotroph 

tumors (147, 406). Such activating somatic GNAS 

mutations are not necessarily restricted to the pituitary, 

but are often part of the McCune-Albright syndrome, 

which is defined by the trias fibrous dysplasia of bone, 

café-au-lait skin pigmentation, and endocrine hyperfunctions 

of variable degree (for review, see Refs. 599, 669). 

Endocrine hyperfunction is due to constitutive activation 

of G s signaling in other endocrine glands, leading to adrenal 

hyperplasia with Cushing syndrome (60, 182), precocious 

puberty (138, 574), or hyperthyroidism (see sect. 

IIIC). In melanocytes, increased G s activity mimics the 

activity of melanocyte stimulating hormone, leading to 

typical café-au-lait hyperpigmentation (334). 

Heterozygous inactivating GNAS mutations result in 

Albright hereditary osteodystrophy (AHO), a congenital 

disorder characterized by obesity, short stature, brachydactyly, 

subcutaneous ossifications, and neurobehavioral 

deficits of variable severity (for review, see Refs. 13, 366, 

599, 669). In addition to these defects, patients with maternally 

inherited mutations show multihormone resistance 

(termed pseudohypoparathyroidism type Ia, 

PHP1a) in tissues with a paternally imprinted GNAS allele, 

such as proximal tubules of the kidney, thyroid, or 

ovaries (209, 242, 414, 723). In these tissues, the effects of 

G s-coupled hormone receptors, like those for parathyroid 

hormone, thyroid stimulating hormones, or the gonadotropins, 

are impaired. Clinically, this results in variable 

degrees of hypocalcemia and hyperphosphatemia, hypothyroidism 

(see also sect. IIIC), and delayed or incomplete 

sexual development and reproductive dysfunction in 

women (13, 366, 599, 669). These abnormalities of the 

reproductive system are easily explained by malfunction 

of receptors for follicle-stimulating hormone and luteinizing 

hormone. In addition, at least in mice, the G s-coupled 

orphan receptor GPR3 is crucially involved in the maintenance 

of meiotic arrest in oocytes (432, 433). 

The phenotype of humans heterozygous for an inactivating 

GNAS mutation is partly reproduced in mice 

carrying a targeted disruption of Gnas exon 2. In these


animals, PTH resistance was only found if the mutation 

was maternally inherited, and only these animals 

showed reduced G� s expression in the renal cortex 

(723). In humans, renal PTH resistance without Albright 

hereditary osteodystrophy (PHPIb) can also be 

due to other GNAS mutations, such as a mutant which 

results in a biallelic paternal imprinting phenotype 

(395), or a mutant unable to interact with the PTH 

receptor (697). Yet another GNAS mutation causes impaired 

signaling via the PTH and TSH receptors, but 

enhanced signaling via the likewise G s-coupled receptor 

for luteinizing hormone, leading to enhanced testosterone 

production. This paradoxical combination of 

gain and loss of function is explained by the fact that 

the underlying GNAS mutation results in a constitutively 

active form of G� s which, however, is temperature 

sensitive. The mutant is stable only at the relatively 

low temperature in the testis, but rapidly degraded 

at 37°C, leading to G� s deficiency (287). With 

respect to pituitary function, patients with inactivating 

GNAS mutations show variable degrees of GHRH resistance 

(415), GH deficiency (210), or hypoprolactinemia 

(88). In accordance with the important role of G s family 

G proteins in lactotrophs and somatotrophs, hypothalamic 

inhibiting hormones, like dopamine or somatostatin, 

act through G i-coupled receptors (311, 536). 

Releasing hormone secretion itself is influenced by 

GPCRs, and several former orphan receptors were recently 

shown to positively regulate releasing hormone 

secretion. Kisspeptins for example, a family of peptides 

derived from the metastasis suppressor gene Kiss-1, were 

shown to enhance hypothalamic gonadotropin-releasing 

hormone secretion via the GPR54 receptor (137, 220, 472), 

and genetic inactivation of GPR54 in mice or mutation in 

humans causes hypogonadotropic hypogonadism (137, 

196, 220, 575). The peptide hormone ghrelin induces pituitary 

growth hormone release not only directly via activation 

of GHS-R on somatotroph cells, but also acts as a 

releasing factor for hypothalamic GHRH (343). Both 

GPR54 and GHS-R are known to activate G q/G 11 family G 

proteins (343, 345), suggesting that releasing hormone 

release is controlled by the same mechanisms as pituitary 

hormone release. In line with this notion, mice lacking 

both G� q alleles and one G� 11 allele selectively in the 

nervous system show severe somatotroph hypoplasia 

with dwarfism due to reduced hypothalamic GHRH production, 

which is probably secondary to impaired GHS-R 

signaling (676). 

B. Pancreatic �-Cells 

The tight regulation of blood glucose levels is mainly 

achieved by the on-demand release of insulin from pancreatic 

�-cells. High glucose levels result in enhanced 


intracellular glucose metabolism with ATP accumulation 

and consecutive closure of ATP-sensitive K � channels, 

leading to the opening of voltage-operated Ca 2� channels 

and Ca 2� -mediated insulin exocytosis (27, 119). In addition 

to the ATP-dependent mechanism of insulin release, 

several GPCRs have been shown to either amplify or to 

inhibit glucose-induced insulin release (for review, see 

Refs. 161, 364, 558), and these receptors and their respective 

ligands play an important role in the regulation of 

islet function by, e.g., the autonomous system (for review, 

see Ref. 7). Neuropeptides and hormones that potentiate 

insulin secretion mainly act though G s-coupled receptors, 

like glucose-dependent insulinotropic polypeptide, secretin, 

cholecystokinin, PACAP, glucagon, vasoactive intestinal 

polypeptide, or glucagon-like peptide-1 (GLP-1) (for 

review, see Refs. 161, 418, 542). The potentiating effect of 

G s on glucose-induced insulin release (576, 608, 609) 

might either be mediated by phosphorylation of voltageoperated 

Ca 2� channels (295) or through the opening of 

nonselective cation channels (275). Transgenic expression 

of a constitutively active G� s mutant in mouse �-cells 

caused increased islet cAMP production and insulin secretion, 

but these changes were only detectable in the 

presence of phosphodiesterase inhibitors, suggesting that 

increased G� s activity is normally compensated by upregulation 

of cAMP degrading enzymes like phosphodiesterases 

(408). Conversely, activation of receptors coupled 

to G i or G o, like the � 2-adrenergic receptor or receptors 

for somatostatin, neuropeptide Y, prostaglandin E 2, or 

galanin, inhibits insulin secretion in a PTX-sensitive manner 

(319, 328, 365, 514, 542). 

Not only G s family members, but also G q/G 11 family G 

proteins, can mediate potentiation of glucose-induced insulin 

release. Acetylcholine released from postganglionic 

parasympathetic nerves or muscarinic agonists act 

through the G q/G 11-coupled M 3 receptor (58, 157) to enhance 

insulin release during the cephalic phase of insulin 

secretion (8, 447, 691). This effect was shown to depend 

on PLC activation and consecutive inositol 1,4,5-trisphosphate 

(IP 3)-mediated intracellular Ca 2� elevation (46, 469, 

726) and PKC activation (22). The exact pathways leading 

to increased insulin secretion are not clear, but activation 

of L-type Ca 2� channels (58), modulation of ATP-sensitive 

K � channels (469), activation of CaM-kinase II (427, 537), 

or enhanced plasma membrane Na � permeability (254) 

have been suggested. In addition to acetylcholine, a variety 

of other local mediators act through G q/G 11-coupled 

receptors to enhance insulin release, like cholecystokinin 

via the CCK 1 receptor (652), bombesin via the BB2 receptor 

(521, 646), arginine vasopressin via the V 1b receptor 

(375, 501, 539), or endothelin via the ET A receptor (224). 

Fatty acids such as palmitate potentiate insulin secretion 

at high glucose levels independently of ATP formation 

(527, 663), and Ca 2� influx via voltage-operated Ca 2� 

channels or intracellular Ca 2� mobilization was suggested

to mediate these effects. The former orphan GPCR GPR40 

was shown to mediate the effects of saturated and unsaturated 

fatty acids (C�6) on intracellular Ca 2� mobilization 

in pancreatic �-cells (70, 296, 346). These effects 

were not PTX sensitive, suggesting that G q/G 11-mediated 

intracellular Ca 2� mobilization was involved (70, 296). 

Another recently deorphanized GPCR probably coupled 

to G q/G 11 is GPR120, which was suggested to be involved 

in fatty acid-induced release of GLP-1 from intestinal 

cells, thereby contributing to GLP-1-mediated insulin release 

(265). 

C. Thyroid Gland/Parathyroid Gland 

Thyroid stimulating hormone (TSH) regulates thyroid 

cell proliferation as well as thyroid hormone synthesis 

and release through the G protein-coupled TSH receptor 

(508). In vitro, the TSH receptor was shown to couple 

to all four G protein families (15, 16, 368), but the major 

signal transduction pathway in vivo seems to be the G s/ 

cAMP cascade, which was shown to activate iodide organification, 

thyroid hormone production, secretion, and 

thyroid cell mitogenesis (153–155, 546). In TSH receptordeficient 

mice, direct stimulation of adenylyl cyclase restores 

the ability to concentrate and organify iodide, suggesting 

that expression of the sodium-iodide symporter is 

controlled by G� s (417). In vitro, overexpression of constitutive 

active G� s in a thyroid cell line (462) or activation 

of G s by transgenic expression of cholera toxin in the 

mouse thyroid (727) caused hyperplasia and increased 

hormone secretion. In line with this, spontaneous activating 

mutations of GNAS can cause thyroid cell hyperfunction 

in humans, leading to hyperthyroidism, goiter, and 

benign adenoma (175, 406, 424, 502). Malignant transformation 

of thyroid cells has also been observed (165, 611, 

711), but seems to require additional mutational or epigenetic 

events (115). Much more frequent than activating 

GNAS mutations are the activating mutations of the TSH 

receptor itself (508), which mainly lead to constitutive 

activation of the G s/cAMP cascade, or, in some cases, to 

activation of both G s- and G q/G 11-coupled pathways (48, 

643). Since the paternal GNAS allele is partly imprinted in 

thyroid cells (209, 394), inactivating GNAS mutants inherited 

from the maternal side cause TSH resistance with 

moderately elevated TSH levels and low thyroid hormone 

levels (171, 381, 382, 670, 719). Mild TSH resistance can 

also be observed in patients with PHP1B due to a GNAS 

mutation with paternal specific epigenotype of both exon 

1A regions (34, 394, 395). In addition to adenylyl cyclase 

activation, TSH stimulates PLC activity (344, 369, 644), 

but the TSH concentrations needed for PLC stimulation 

are 100-fold higher than those needed for adenylyl cyclase 

stimulation (643). 

The parathyroid gland controls Ca 2� homeostasis 

through parathyroid hormone (PTH), which enhances 



Ca 2� (re)absorption in gut and kidney, as well as Ca 2� 

release from bone. High extracellular Ca 2� concentrations 

activate the G protein-coupled extracellular Ca 2� 

sensing receptor (CaR), leading to inhibition of PTH production 

and secretion in parathyroid cells (for review, see 

Refs. 74, 268, 661). Activation of the CaR causes a PTXinsensitive 

(240) stimulation of PLC-� isoforms, with consecutive 

increments in inositol phosphates, DAG, and 

intracellular Ca 2� levels (73, 75, 478). In addition, an 

activation of phospholipases A 2 and D (333) as well as a 

PTX-sensitive suppression of cAMP formation was observed 

(98). These studies suggested that the CaR couples 

both to G q/G 11 and G i/G o family G proteins, and this 

notion was supported by the finding that CaR activation 

induced incorporation of radiolabeled GTP into G� q and 

G� i in Madin-Darby kidney (MDCK) cells, which endogenously 

express low levels of the CaR (25). The fact that 

increased intracellular Ca 2� levels result in decreased, 

not increased, hormone release is quite exceptional, and 

parathyroid cells are, besides renin-secreting juxtaglomerular 

cells (572), the only endocrine cells showing such 

inverse coupling. However, the molecular mechanism underlying 

Ca 2� -mediated inhibition of PTH secretion is not 

understood (for review, see Refs. 74, 86, 268, 661). 

D. Regulation of Carbohydrate and 

Lipid Metabolism 

Normal blood glucose levels are maintained both by 

regulating the activity of enzymes involved in carbohydrate 

metabolism and by controlling glucose uptake into 

peripheral tissues. Insulin is a major regulator of both 

processes, but also a variety of GPCR agonists, like catecholamines 

and glucagon, contribute to glucose homeostasis. 

In hepatocytes, activation of G s-coupled receptors 

like the � 2-adrenergic receptor or glucagon receptors 

causes PKA-mediated phosphorylation of key enzymes 

which regulate glycogen synthesis, glycogen breakdown, 

glycolysis, or gluconeogenesis (167, 168). Together, these 

changes lead to enhanced hepatic glucose release. Comparable 

changes can be induced by activation of G q/G 11coupled 

receptors like the � 1-adrenergic receptor or receptors 

for vasopressin and angiotensin, and these effects 

are probably mediated by Ca 2� /calmodulin-dependent alteration 

of enzymatic activity (167, 168). In the periphery, 

glucose uptake into skeletal muscle and adipocytes is 

mediated by translocation of glucose transporter subtype 

4 (GLUT4) from intracellular vesicles to the plasma membrane 

(665). A variety of GPCRs have been demonstrated 

to modify insulin-induced GLUT4 translocation, and even 

a direct interaction between the insulin receptor and heterotrimeric 

G proteins was suggested (412). Heterozygous 

GNAS-deficient mice show, in addition to other metabolic 

abnormalities (for effects on lipolysis, see below), an


increased sensitivity towards insulin, which was attributed 

to enhanced insulin-dependent glucose uptake into 

the skeletal muscle (104, 721). In line with this, transgenic 

expression of a constitutively active mutant of G� s 

(G� sQ227L) in fat, liver, and skeletal muscle decreased 

glucose tolerance (284), suggesting that G� s-mediated signaling 

negatively regulates insulin-induced GLUT4 translocation. 

In contrast, G i family G proteins seem to facilitate 

insulin effects. Pretreatment of isolated adipocytes 

and soleus muscle with PTX results in reduced insulinstimulated 

glucose uptake (111, 325), and mice in which 

G� i2 was downregulated in liver and adipose tissue using 

an antisense RNA approach show insulin resistance with 

hyperinsulinemia, decreased glucose tolerance, and insulin 

resistance (459–461). In the latter mice, both insulininduced 

GLUT4 translocation to the plasma membrane 

and activation of glycogen synthase and antilipolytic mediators 

were impaired (461). The decrease in G� i2 levels 

was accompanied by an increase in protein tyrosine phosphatase-1B 

(PTP-1B) activity, an enzyme known to dephosphorylate 

phosphorylated tyrosine residues on the 

insulin receptor and on insulin receptor substrate-1. This 

suggests that the inhibition of insulin signaling in mice 

with reduced G� i2 levels is due to disinhibition of PTP-1B 

(461). Mice expressing a constitutively active mutant of 

G� i2 (G� i2Q205L) in fat, liver, and skeletal muscle displayed 

reduced fasting blood glucose levels and increased 

glucose tolerance (103). Adipocytes from these mice 

showed enhanced insulin-induced glucose uptake and 

GLUT4 translocation, as well as increased PI 3-kinase and 

Akt activities (596). In addition, PTP-1B is suppressed in 

G� i2 overexpressing mice (626), and streptozotocin-induced 

diabetic changes are ameliorated (732). Up to now 

it is not clear at which levels the insulin receptor-mediated 

pathway interacts with the G i-mediated pathway. It 

was suggested that G i/G o family G proteins physically 

interact and are phosphorylated by the activated insulin 

receptor (for review, see Ref. 510). In addition, G i/G o 

might be involved in insulin-mediated autophosphorylation 

of the insulin receptor (351). 

Data from 3T3 L1 adipocytes strongly point to an 

involvement of G q/G 11 family G proteins in basal and 

insulin-induced GLUT4 translocation. Overexpression of 

wild-type or constitutively active G� q increased basal 

GLUT4 translocation (290, 326), while microinjection of 

G� q/G� 11 antibodies or RGS2 protein inhibited insulininduced 

GLUT4 translocation (290, 326). In line with these 

findings, inhibition of GRK2, a negative regulator of G q/ 

G 11 signaling, increased insulin-stimulated GLUT4 translocation, 

while adenovirus-mediated overexpression of 

GRK2 reduced translocation as well as 2-deoxyglucose 

uptake (637). The exact mechanisms underlying G q/G 11mediated 

GLUT4 translocation are not fully understood. 

Several G q/G 11-coupled receptors are able to stimulate 

glucose uptake via GLUT4 translocation, such as recep- 


tors for endothelin-1 (ET-1), norepinephrine, platelet-activating 

factor, or bradykinin (335, 336, 698). Microinjection 

of an anti-G� q/G� 11 antibody or of RGS2 protein 

causes inhibition of ET-1-induced GLUT4 translocation 

(289). Of note, chronic ET-1 treatment inhibits insulinstimulated 

glucose uptake and GLUT4 translocation in 

3T3-L1 adipocytes, and decreased tyrosine phosphorylation 

of insulin receptor substrates was suggested to mediate 

this heterologous desensitization (292). The G q/G 11mediated 

effect on GLUT4 translocation was shown to be 

PI 3-kinase dependent in some (289, 290) but not in all 

studies (59, 326). Recently, a role for the ADP ribosylation 

factor 6 and the Ca 2� -activated tyrosine kinase Pyk2 was 

suggested (59, 371, 506). 

Other examples for G protein-regulated metabolic 

processes are adipocyte lipolysis and lipogenesis. Activation 

of G s-coupled receptors like those for catecholamines, 

ACTH, glucagons, TSH, or PTH enhances 

lipolysis via PKA-dependent phosphorylation of hormonesensitive 

lipase (274, 401, 606). In adipocytes from patients 

heterozygous for an inactivating GNAS mutation, 

the lipolytic effect in response to epinephrine is impaired, 

and this was suggested to contribute to obesity observed 

in AHO patients (87). Heterozygous disruption of Gnas 

exon 2 in mice causes not only enhanced insulin sensitivity 

(721), but also a variety of other metabolic defects that 

depend on the parental origin of the inherited mutation 

(722). While mice with a maternally inherited inactivating 

mutation of the Gnas gene are obese and hypometabolic, 

paternally inherited Gnas mutations cause abnormal leanness 

with decreased serum, liver, and muscle triglycerides, 

and lipid oxidation in adipocytes is enhanced (104, 

722). Since these mice have increased urine norepinephrine 

excretion, it was suggested that increased sympathetic 

stimulation of adipocytes caused the changes in 

lipid metabolism (104, 722). The reason for the restriction 

to paternally inherited mutations is not completely clear. 

Deletion of Gnas exon 2 does not only affect the expression 

of G� s, but also of alternative gene products like 

XL� s (Fig. 3) (245, 667). An involvement of XL� s in the 

hypermetabolic phenotype seems likely for three reasons. 

First, XL� s is only expressed from the paternal allele 

(104) and is therefore well suited to explain a paternally 

inherited phenotype. Second, XL� s-deficient mice show a 

phenotype similar to paternally exon 2-deficient mice 

(522). Third, mice with paternal inheritance of a Gnas 

exon 1 deletion, which does not affect XL� s expression, 

do not show the respective phenotype (668). Interestingly, 

studies in XL� s-deficient mice suggest that G� s and 

XL� s can exert opposing effects on whole body metabolism 

(522, 668). In addition to G s family G proteins, also 

the G q/G 11 family was implicated in the regulation of 

lipolysis. Expression of antisense RNA to G� q in liver and 

white fat caused hyperadiposity, which was suggested to

e attributed to an impaired lipolytic response towards 

� 1-adrenergic agonists (198). 

Inhibition of adipocyte lipolysis is mediated by the 

insulin receptor or by activation of G i-coupled receptors 

like the � 2-adrenergic receptor, receptors for adenosine 

or prostaglandin (401) or the recently deorphanized receptor 

for nicotinic acid, GPR109A (HM74a/PUMA-G) 

(634). G� i was suggested to be directly involved in the 

antilipolytic effect of insulin, since insulin-dependent inhibition 

of lipolysis and activation of glucose oxidation in 

adipocytes were shown to be PTX sensitive (219). 

IV. IMMUNE SYSTEM 

A. Leukocyte Migration/Homing 

Directed cell movement in response to an increased 

concentration of chemoattractant underlies the correct 

targeting of leukocytes to lymphatic organs during antigen 

surveillance and also allows them to migrate to sites 

of infection and/or inflammation (for review, see Refs. 

653, 694). Known lymphocyte chemoattractants either belong 

to the large family of chemokines (355, 500) or to the 

lysophospholipid family, like sphingosine-1-phosphate 

(S1P) or lysophosphatidic acid (LPA) (123, 221, 282). Both 

chemokine and lysophospholipid receptors are GPCRs. 

While chemokine receptors primarily act through G i family 

G proteins (355), lysophospholipid receptors activate 

G i,G 12/G 13, and G q/G 11 family G proteins depending on 

type and activation state of the respective cell (377, 584, 

612). 

Inactivation of G i family G proteins by PTX pretreatment 

strongly impairs lymphocyte migration in vitro (28, 

598) and causes defective homing to spleen, lymph nodes, 

and Peyer’s patches in vivo (31, 124, 597, 662), suggesting 

that G i family G proteins are involved in these processes. In 

line with this, inactivation of G i by transgenic expression of 

the S1 subunit of PTX in murine thymocytes resulted in 

accumulation of mature T cells in the thymus, with greatly 

reduced levels of T cells in peripheral lymphatic organs (91, 

92). To investigate the role of G i-mediated signaling in more 

detail, mouse lines carrying inactivating mutations of G� i 

subtypes were generated. Both G� i2 and G� i3 are expressed 

in the murine thymus (91), but only inactivation of G� i2 

mimicked the phenotype of PTX expressing mice with respect 

to thymic accumulation of mature T cells. Neither 

G� i2- nor G� i3-deficient mice showed defects in T cell homing 

to the periphery (552), suggesting that the homing defects 

induced by PTX probably result from the combined 

inactivation of G i2 and G i3. 

Despite the predominant role of G i signaling in chemokine-induced 

lymphocyte migration, an involvement of 

G q/G 11 family G proteins was suggested by a variety of in 

vitro studies (11, 21, 353, 590, 716). In contrast to other 



tissues, hematopoietic cells do not only express the 

�-subunits G� q and G� 11, but also G� 15, which corresponds 

to human G� 16 (17, 683). Mice deficient for G� 11, 

G� 15, or both G� q and G� 15 were normal under basal 

conditions and after antigenic challenge, and only a minor 

signaling defect in response to complement C5a was 

found in G� 15-deficient macrophages (132). 

The G 12/G 13 effector RhoA was repeatedly shown 

to be involved in the regulation of lymphocyte adhesion 

and migration (367, 631), but direct evidence for an 

involvement of the G 12/G 13 family is still lacking. Indirect 

evidence for a role of G 13 in lymphocyte migration 

comes from studies in Lsc-deficient mice. The murine 

Rho-specific guanine nucleotide exchange factor Lsc 

(p115RhoGEF in humans) is expressed exclusively in hematopoietic 

cells and couples G� 13 to the activation of 

RhoA (236). Lsc-deficient mice show impaired agonistinduced 

actin polymerization and motility, as well as abnormal 

B-cell homing and altered T- and B-cell proliferation 

(214). Defective migration was also observed in mice 

lacking the proton-sensing receptor G2A (465), which was 

shown to couple to G� 13 (316). G2A-deficient macrophages 

(659) and T cells (533) showed reduced migration 

towards lysophosphatidylcholine (LPC), while G2A overexpression 

in a macrophage cell line enhanced migration 

towards LPC (533, 715). How LPC effects are affected by 

the absence of G2A is currently not clear (690). In the 

latter cells, LPC-induced chemotaxis was inhibited by 

overexpression of dominant negative mutants of G� q/ 

G� 11 or G� 12/G� 13, as well as expression of RGS domains 

or GRK2 (specific for G q/G 11) or of p115RhoGEF (specific 

for G 12/G 13), while PTX treatment was without effect 

(715). 

Also neutrophils respond to a variety of chemoattractants, 

such as N-formyl-Met-Leu-Phe (fMLP), C5a, platelet 

activating factor (PAF), or the chemokine interleukin 

(IL)-8, with polarization and directed migration. This effect 

was shown to be PTX sensitive (43, 217, 577, 598) and 

to be mainly mediated via ��-subunits (479, 480) (Fig. 8). 

Lentiviral-mediated knockdown of different G protein 

subunits in a macrophage cell line revealed that complement 

C5a-induced migration critically depends on G� 2, 

but not on G� 1,G� i2, orG� i3 (286). Intracellular effectors 

of G�� in neutrophils are the �-isoform of PI 3-kinase 

(PI3K�) and the �2- and �3-isoforms of phospholipase C 

(PLC-�2, -�3). While neutrophils from mice lacking 

PLC-�2 and -�3 show normal, or even enhanced, chemotactic 

responses (388), migration of PI3K�-deficient neutrophils 

was severely impaired (266, 388, 566). Moreover, 

PI3K�-deficient neutrophils failed to accumulate at sites 

of inflammation in a septic peritonitis model (266), suggesting 

that PI3K� mediates chemotactic responses both 

in vitro and in vivo. In addition to PI3K�, RhoA activity 

seems to be required for fMLP-induced neutrophil chemokinesis 

and chemotaxis (review in Ref. 484), and espe-


FIG. 8.G i family G proteins are centrally involved in neutrophil 

migration and activation and mediate their effects via the �2- and 

�3-isoforms of phospholipase C (PLC-�2/�3), phosphoinositide 3-kinases 

(PI-3-K), or the RacGEF P-Rex1. Btk, Bruton’s kinase; DAG, 

diacylglycerol; IP 3, inositol 1,4,5-trisphosphate; PIP 2, phosphatidylinositol 

4,5-bisphosphate; PI(3,4,5)P 3, phosphatidylinositol 3,4,5-trisphosphate; 

PKC, protein kinase C. 

cially the deadhesion of the uropod was attributed to 

RhoA (12, 397). Interestingly, fMLP receptor-mediated 

chemotaxis of HL60 cells was recently suggested to involve 

not only G i, but also G 12/G 13 (702). In these cells, 

activation of G i defined “frontness” by activating PI3K and 

Rac, whereas activation of G 12/G 13 defined “backness” by 

inducing RhoA-dependent actomyosin interaction (702). 

B. Immune Cell Effector Functions 

Activation of immune cells by antigen contact initiates 

complex signaling cascades leading to proliferation, 

differentiation, or initiation of effector functions like cytokine 

production, mediator release, phagocytosis, etc. 

Although these functions are not directly G protein mediated, 

G proteins might have important modulatory roles 

(312, 400). 

� 

In neutrophils, chemoattractant-induced O2 formation 

is mediated via Gi-coupled receptors (39) and is 

strongly impaired both in neutrophils from mice lacking 

PLC-�2 and -�3 (388, 695, 699) and in PI3K�-deficient 

neutrophils (266, 388, 566). PI3K-mediated formation of 

phosphatidylinositol 3,4,5-trisphosphate (PIP3) was shown 

to activate the small GTPase Rac, which contributes to 

neutrophil migration by actin polymer formation in the 

� 

leading edge (540, 653) and to O2 formation by NADPH 


oxidase activation (144). Recently, a new Rac GEF termed 

P-Rex1 was shown to mediate Rac activation in response 

to PIP 3 and G�� in neutrophils (672). 

In lymphocytes, the balance between the T H1-driven 

cellular immunity and T H2-driven humoral response is 

mainly shaped by the cytokine pattern present during T 

helper cell activation. PTX has long been known to promote 

T H1 responses (246, 270, 464), and this was suggested 

to be due to a negative regulation of IL-12 production 

by G i, especially in dendritic cells (246, 279). Mice 

lacking G� i2 develop a diffuse inflammatory colitis resembling 

ulcerative colitis in humans (277, 552), and adenocarcinomas 

secondary to chronic inflammation were often 

observed (552). In these mice, levels of proinflammatory 

T H1-type cytokines and of IL-12 were increased (277), 

and these changes clearly preceded the onset of bowel 

inflammation (497, 498). In addition, antigen presenting 

cells like CD8a � dendritic cells showed a highly increased 

basal production of IL-12 (246), suggesting that colitis in 

these mice is a T H1-driven disease and that production of 

proinflammatory T H1 cytokines is constitutively suppressed 

through a G i-mediated pathway. Accordingly, activation 

of G s-mediated signaling opposes these effects. 

Cholera toxin, which activates G s by ADP-ribosylation, 

can be used as an adjuvant to promote T H2 responses 

(419, 687, 707), and systemic administration of cholera 

toxin during induction of T H1-based autoimmune diseases 

can shift the immune response to the nonpathogenic T H2 

phenotype (610). In general, the G s family was suggested 

to attenuate proinflammatory signaling, but direct evidence 

is lacking. In vitro, application of cAMP (62, 321, 

671) or activation of typically G s-coupled receptors, like 

those for vasoactive intestinal polypeptide or PACAP 

(135, 201), was shown to inhibit immune cell functions. 

Immune cells from mice lacking the G s-coupled adenosine 

A 2A receptor respond with enhanced cytokine transcription 

and NF�B activation to activation of Toll-like 

receptors (404), and activation of G s by cholera toxin 

inhibits signaling in T cells (476, 595) or natural killer cells 

(678). 

The relevance of G q/G 11 and G 12/G 13 family G proteins 

in lymphocyte activation and proliferation is unclear. 

In vitro studies suggested an involvement of both 

families in the activation of Bruton’s tyrosine kinase, a 

protein that is required for normal B-cell development and 

activation (42, 309, 402). The G q/G 11 family, especially 

human G� 16, has been implicated in T-cell activation in a 

variety of in vitro studies (392, 603, 734), but the physiological 

relevance of these findings is unclear. In vivo, no 

obvious immunological defects were observed in 

G� 11 �/� ,G�15 �/� ,orG�15 �/� ;G�q �/� mice (132). However, 

after antigenic challenge, G� q-deficient mice showed 

impaired eosinophil recruitment to the lung, probably due 

to an impaired production of granulocyte macrophage 

colony stimulating factor GM-CSF by resident airway leu-

kocytes (56). Indirect evidence for a role of G q/G 11 and/or 

G 12/G 13 in T-cell activation comes from RGS2-deficient 

mice, which show impaired T-cell proliferation and IL-2 

production after T-cell receptor stimulation, as well as 

defective antiviral immunity in vivo (499). Inactivation of 

the murine TxA 2 receptor, which is typically coupled to 

G q/G 11 and/or G 12/G 13 family G proteins (337, 492), caused 

a lymphoproliferative syndrome due to prolonged 

T-cell/DC interaction (317). Genetic inactivation of the 

proton-sensitive G2A receptor (465), which was shown to 

activate G 12/G 13, causes a late-onset autoimmune syndrome 

in mice (372), suggesting that these G proteins may 

be involved in the regulation of lymphocyte activation. 

V. NERVOUS SYSTEM 

G proteins play multiple roles in the nervous system 

as most neurotransmitters also activate G protein-coupled 

metabotropic receptors to modulate neuronal activity. 

In contrast to ionotropic receptors, GPCRs that are 

present pre- and postsynaptically mediate comparatively 

slow responses. Only a few well-studied examples are 

described below. 

A. Inhibitory Modulation of Synaptic Transmission 

The regulation of neurotransmitter release at presynaptic 

terminals is an important mechanism underlying the 

modulation of synaptic transmission in the nervous system. 

Inhibitory regulation of neurotransmitter release is 

mediated by various GPCRs like � 2-adrenoceptors, �- and 

�-opioid receptors, GABA B receptors, adenosine A 1,or 

endocannabinoid CB 1-receptors. These receptors have in 

common that they couple to G proteins of the G i/G o 

family. A major mechanism by which these G proteins 

mediate the inhibition of transmitter release is the inhibitory 

modulation of the action potential-evoked Ca 2� entry 

to the presynaptic terminal which is required to trigger 

neurotransmitter release. N- and P/Q-type calcium channels 

that are concentrated at nerve terminals as well as 

R-type calcium channels have been shown to be inhibited 

via G i/G o-coupled receptors (145). This inhibition is due to 

the interaction of the G protein ��-complex with the 

� 1-subunit of Ca v2.1–2.3 (89, 420). The �-subunit of the 

channel as well as strong depolarization can reduce this 

inhibition (61, 439). Most G�� combinations are similarly 

effective in inhibiting channels of the Ca v2 family (202, 

288, 557). There is some evidence that ��-mediated inhibition 

of Ca v2 channels is not the only mechanism 

through which GPCRs mediate inhibition of neurotransmitter 

release (449). Also, G protein-coupled inwardly 

rectifying K � channels (GIRKs) are localized at presynaptic 

terminals; however, their physiological role in regulation 

of transmitter release from presynaptic terminals is 



less clear (156, 524). GIRKs are well-established effectors 

for G protein ��-subunits (113, 356, 398, 718), and most 

G�� combinations appear to be similarly effective in activating 

GIRKs (681, 708). There is also increasing evidence 

that the G��-mediated inhibition of neurotransmitter 

release at the presynaptic terminus involves mechanisms 

downstream of the regulation of Ca 2� (51). This 

may involve the direct interaction between G�� and the 

core vesicle fusion machinery as suggested by the observation 

that G�� can directly bind to SNARE proteins like 

syntaxin and SNAP25 as well as cysteine string protein 

(CSP) (50, 51, 305, 410). Evidence exists that presynaptic 

Ca 2� channels, syntaxin1, and the �-subunit of G o are 

components of a functional complex at the presynaptic 

nerve terminal release site (384, 602). 

Both G i-type G proteins as well as G o are highly 

abundant in the nervous system. Mice lacking the �-subunit 

of G o are smaller and weaker than their littermates 

and have a greatly reduced life expectancy (308, 639). In 

addition, these animals have tremors and occasional seizures, 

and they show an increased motor activity with an 

extreme turning behavior. G� o-deficient mice have also 

been shown to be hyperalgesic (308). When neuronal cells 

from G� o-deficient mice were analyzed by electrophysiological 

methods for the regulation of GIRKs and voltagedependent 

Ca 2� channels through GPCRs, it was found 

that the recovery kinetics after agonist washout were 

much slower in the absence of G� o. However, current 

modulation via various receptors was as effectively as in 

wild-type cells (225, 308). This indicates that other G 

proteins especially G i-type G proteins that are activated 

by the same receptors can compensate for G o deficiency. 

B. Modulation of Synaptic Transmission by the 

G q/G 11-Mediated Signaling Pathway 

In the nervous system, the G proteins G q and G 11 are 

widely expressed (622), and they are involved in multiple 

pathways that modulate neuronal function. The modulation 

of synaptic transmission has best been described at 

the parallel fiber (PF)-Purkinje cell (PC) synapse in the 

cerebellum. At the PF-PC synapse, G q/G 11 mediate the 

effects of metabotropic glutamate group 1 receptors 

(mGluR1). The G q/G 11-mediated IP 3-dependent transient 

increase in the dendritic Ca 2� concentration, which does 

not require changes in the membrane potential (178, 621), 

is important for the induction of long-term depression 

(LTD) at the PF-PC synapse (452). LTD in turn is believed 

to be one of the cellular mechanisms underlying cerebellar 

motor learning (66). Interestingly, while G� q-deficient 

mice develop an ataxia with clear signs of motor coordination 

deficits, G� 11-deficient animals show only very 

subtle defects in motor coordination (237, 489). A detailed 

comparison of both mouse lines showed that Ca 2� re-


sponses to mGluR1 activation were absent in G� q-deficient 

mice, whereas they are indistinguishable between 

wild-type and G� 11-deficient animals (237). However, synaptically 

evoked LTD was decreased in G� 11-deficient 

animals, but to a lesser extent than in G� q-deficient mice. 

The predominant role of G q in Purkinje cells can be 

explained by the higher expression compared with G� q 

(489). In fact, quantitative single-cell RT-PCR analysis 

showed that Purkinje cells express at least 10-fold more 

G� q than G� 11 (237). 

Lack of G� q also results in a defect in the regression 

of supernumerary climbing fibers innervating Purkinje 

cells in the third postnatal week. This process is believed 

to be due to a defect in the modulation of the PF-PC 

synapse. Similar cerebellar phenotypes as in G� q-deficient 

mice have been described in mice lacking the mGluR1 (9, 

323) as well as in mice lacking the � 4-isoform of PLC, 

which is predominantly expressed in the rostral cerebellum 

(324, 453). Interestingly mGluR1, G� q, and PLC-�4 

can be found colocalized in dendritic spines of PCs (324, 

622, 664), suggesting that they are components of a signaling 

cascade involved in the modulation of the PF-PC 

synapse. 

Interestingly, hippocampal synaptic plasticity is 

equally impaired in G� q- and G� 11-deficient mice (451). 

However, mGluR-dependent long-term depression in the 

hippocampal CA1-region was absent in G� q-deficient mice 

but appeared to be unaffected in mice lacking G� 11 (340). 

Similarly, suppression of slow afterhyperpolarizations via 

muscarinic and metabotropic glutamate receptors was 

nearly abolished in G� q-deficient mice but was unchanged 

in mice lacking G� 11 (350). 

Besides the voltage-dependent, G protein-mediated 

inhibition of calcium channels via G�� (see above), functional 

studies in calyx-type nerve terminals and in sympathetic 

neurons have identified a voltage-insensitive inhibition 

of calcium currents via metabotropic receptors 

that is believed to involve G q/G 11 (322, 449). How G q/G 11 

activation can lead to inhibition of voltage-dependent calcium 

channels is not clear. However, recent evidence suggests 

that the depletion of phosphatidylinositol 4,5-bisphosphate 

(PIP 2), the substrate of PLC plays a role (200). 

There is also evidence that activation of G q/G 11mediated 

signaling on the postsynaptic site is involved 

in the induction of retrograde signaling via the endocannabinoid 

system. G q/G 11-coupled receptors like 

group I mGluRs as well as muscarinic M 1 receptors can 

lead to the activation of the retrogradely acting cannabinoid 

system by stimulating the formation of endocannabinoids 

(136, 189, 380, 409). 

C. Roles of G z and G olf in the Nervous System 

G s is the ubiquitous G protein that couples receptors 

in a stimulatory fashion to adenylyl cyclases. How- 

ever, in a few tissues the G protein G olf is the predominant 

G protein that couples receptors to adenylyl cyclase. 

Apart from the olfactory system (see below), 

G� olf expression levels exceed those of G� s also in a 

few other defined brain regions like the nucleus accumbens, 

the olfactory tubercle, and the striatum (40, 120, 

737). In the striatum, G olf appears to be critically involved 

in dopamine (D 1) and adenosine (A 2) receptormediated 

effects (258, 737). Data from various laboratories 

show that in the striatum, the dopamine D 1 receptor, 

G� olf and adenylyl cyclase type V as well as the 

G protein � 7-subunit are coexpressed. Strikingly, mice 

lacking either of these signaling components show 

clear signs of motor abnormalities (40, 298, 573, 703). 

Mice lacking adenylyl cyclase V show an attenuated 

D 1-receptor/G olf-mediated adenylyl cyclase activation 

in the striatum (298). G� 7-deficient mice have strongly 

reduced levels of striatal G� olf, and activation of adenylyl 

cyclase via dopamine receptors is abolished in the 

striatal cells (573). Thus, in rodents, striatal D 1 receptors 

appear to activate adenylyl cyclase V through a G 

protein containing G� olf and �7. In humans, it has recently 

been shown that G� olf expression is markedly 

diminished in the putamen of patients with Huntington 

disease, while the putamen of patients with Parkinson 

disease showed significantly increased levels of G� olf 

and G� 7 (120). 

The G protein G z is a member of the G i/G o family. It 

shares with other G i/G o family members the ability to 

inhibit adenylyl cyclase (176, 267). It is expressed primarily 

in brain, retina, adrenal medulla, and platelets. G� zdeficient 

mice are viable and have no major phenotypical 

abnormalities. However, G� z deficiency results in an abnormal 

response to certain psychoactive drugs (253, 713). 

This includes a considerably pronounced cocaine-induced 

increase in locomotor activity as well as a reduction 

in the short-term antinociceptive effects of morphine 

(713). In addition, G� z-deficient animals develop significantly 

increased tolerance to morphine (374). Interestingly, 

the behavioral effects of catecholamine reuptake 

inhibitors that are used as antidepressant drugs were 

abolished in mice lacking G� z (713). While mice lacking 

G� z clearly indicate that G z plays a role in the nervous 

system and is involved in various drug responses, the 

function of G z on a cellular level in the nervous system 

remains unclear. 

VI. SENSORY SYSTEMS 


G protein-mediated signal transduction processes 

mediate the perception of many sensory stimuli. Odors, 

light, and especially sweet and bitter taste substances act 

directly on GPCRs that modulate the activity of primary 

sensory cells via often very specialized heterotrimeric G 

proteins.

A. Visual System 

The human retina contains two types of photoreceptor 

cells, rods and cones. While rods mediate mainly 

achromatic night vision and contain one type of GPCR, 

rhodopsin, cones are responsible for chromatic day vision 

and contain three GPCRs (opsins), which are sensitive to 

different parts of the visible light spectrum. Rhodopsin 

and opsins are coupled to different but closely related 

heterotrimeric G proteins. Rod-transducin (G t-r) and 

cone-transducin (G t-c), which mediate the effects of rhodopsins 

and opsins, respectively, couple these receptors 

in a stimulatory manner to cGMP-phosphodiesterase 

(PDE) by binding and sequestering the inhibitory �-subunit 

of the retinal type 6 PDE (PDE6). Activation of PDE 

lowers cytosolic cGMP levels leading to a decreased open 

probability of cGMP-regulated cation channels in the 

plasma membrane, which eventually results in hyperpolarization 

of the photoreceptor cells (24). In mice lacking 

G� t-r, the majority of retinal rods does not respond to light 

any more, and these animals develop mild retinal degeneration 

with increasing age (84). To ensure an adequate 

time resolution of the light signal, the transducin-mediated 

signaling process initiated by light-induced receptor 

activation requires an efficient termination mechanism. At 

least three proteins contribute to the rapid deactivation of 

transducin by increasing its GTPase activity: RGS9 and 

G� 5L, which form a complex, and the �-subunit of the 

transducin effector cGMP-PDE (24). In mice lacking G� 5, 

the levels of RGS9 and other G protein �-like (GGL) 

domain RGS proteins in various tissues including retina 

are drastically reduced, suggesting that the formation of 

the RGS9 G� 5 complex is required for expression and 

function of RGS9 (100). Animals lacking G� 5 or RGS9 

show a strongly impaired termination of transducin-mediated 

signaling (99, 352, 407). 

The light-induced hyperpolarization of photoreceptor 

cells results in a decreased release of glutamate. Glutamate 

released from photoreceptor cells acts on two 

classes of second-order neurons in the retina, one that 

depolarizes in response to glutamate most likely via ionotropic 

glutamate receptors (OFF bipolar cells) and another 

that hyperpolarizes (ON bipolar cells). ON bipolar 

cells are in the absence of light inhibited by glutamate 

released from rods and cones, and this effect is mediated 

by the metabotropic glutamate receptor mGluR6. Lightinduced 

hyperpolarization of rods results in decreased 

glutamate release and disinhibition of ON bipolar cells 

due to a decreased activation of mGluR6. In mice lacking 

mGluR6 or the G� o splice variant G� o1, the modulation of 

ON bipolar cells in response to light is abolished (142, 143, 

425), indicating that G o is the principle mediator of glutamate-induced 

inhibition of ON bipolar cells, which occurs 

especially in the absence of light. The retina-specific 

RGS protein Ret-RGS1 is localized in the dendritic tips of 


ON bipolar cells together with mGluR6 and G� o1 and may 

play a critical role in increasing the deactivation of G o1 

resulting in an acceleration in the rising phase of the light 

response of the ON bipolar cells. This mechanism has 

been suggested to match the kinetics of ON bipolar cell 

activation to that of the OFF bipolar cells that arises 

directly from ligand-gated channel activation by glutamate 

(141). 

B. Olfactory/Pheromone System 


Chemosensation by the olfactory system is based on 

the expression of a huge variety of GPCRs specifically in 

the olfactory epithelium. Individual olfactory sensory neurons 

appear to often express only one olfactory receptor, 

and olfactory sensory neurons expressing one receptor 

type converge to the same subgroup of glomeruli in the 

olfactory bulb (457, 548). Rodents have �1,000 different 

olfactory receptors, whereas the number in humans is 

considerably smaller and has been estimated to be �350 

(457). Despite this remarkable diversity on the level of the 

receptor, the olfactory GPCRs appear to employ the same 

G protein-mediated signal transduction pathway in olfactory 

sensory neurons. The G protein G olf is centrally 

involved in signaling by olfactory receptors in response to 

odorant stimuli, and G� olf-deficient mice are anosmic exhibiting 

dramatically reduced electrophysiological responses 

to all odors tested (40). G olf, a G protein related 

to G s, couples olfactory receptors in the cilia to adenylyl 

cyclase III, resulting in the increased formation of cAMP. 

cAMP then activates a cyclic nucleotide-gated (CNG) cation 

channel consisting of three different subunits, 

CNGA2, CNGA4, and CNGB1. The increase in cellular 

Ca 2� activates a Ca 2� -activated Cl � channel that further 

depolarizes the cell membrane (457, 548). Most G� olfdeficient 

pups die a few days after birth due to insufficient 

feeding. Rare surviving animals exhibit inadequate maternal 

behavior resulting in the death of all pups born to 

G� olf-deficient mothers. This indicates that normal nursing 

and mothering behavior in rodents is greatly dependent 

on an intact olfactory system (40). The fundamental 

role of this signaling pathway is underscored by the anosmic 

phenotype found not only in mice lacking G� olf, but 

also adenylyl cyclase (693) as well as in mice lacking the 

subunits of the olfactory CNG channel (30, 76, 731). 

A second olfactory system called the accessory olfactory 

system or the vomeronasal system exists in most 

mammals (152, 330). The peripheral sensory structure of 

this system, the vomeronasal organ, is localized at the 

bottom of the nasal cavity. The vomeronasal system responds 

to pheromones that mediate defined effects on 

individuals of the same species and modulate social, aggressive, 

reproductive, and sexual behaviors. In the vomeronasal 

organ, two families of GPCRs, which in mice


consist of �150 members each, have been identified. The 

V1 receptor family is expressed in vomeronasal sensory 

neurons together with the G protein G i2, whereas the V2 

receptor family is expressed in a different population of 

neurons that coexpresses the G protein G o (428). In humans, 

no intact genes coding for V2 family receptors have 

been found, and most V1 receptor genes are pseudogenes, 

suggesting that the function of the vomeronasal organ of 

rodents is not fully preserved in humans and higher primates. 

Similar to the olfactory receptors, individual members 

of the V1 and V2 receptor families appear to be 

specifically expressed in individual sensory neurons that 

project to a small group of glomeruli in defined regions of 

the accessory olfactory bulb. The striking coexpression of 

V1 receptor family members and G i2 and of V2 receptor 

family members and G o suggests that these G proteins 

mediate the cellular effects induced by activation of the 

respective pheromone receptors. Consistent with this, 

G� i2-deficient mice have a reduced number of vomeronasal 

sensory neurons that normally express G� i2 and show 

alterations in the behaviors for which an intact vomeronasal 

organ is believed to be required like maternal aggressive 

behavior as well as aggressive behavior in males 

exposed to an intruder (486). In mice lacking G� o apoptotic 

death of vomeronasal sensory cells which usually 

express G� o has been observed (623). Despite these behavioral 

and anatomical abnormalities in G� i2- and G� odeficient 

mice, a direct involvement of G� i2 in signaling of 

V1 receptor-expressing cells and of G� o in V2 receptorexpressing 

cells has not been demonstrated so far. The 

transient receptor potential channel TRP2, which is expressed 

in vomeronasal sensory neurons, has been identified 

as a critical downstream mediator of the signal 

transduction pathway in vomeronasal sensory neurons 

(383, 605). 

C. Gustatory System 

Unlike the olfactory system, chemosensation by 

the gustatory system involves only in part G proteinmediated 

signal transduction mechanisms. The taste 

qualities sweet, bitter, and amino acid (umami) signal 

through GPCRs, whereas salty and sour tastants act 

directly on ion channels (391). During recent years, two 

families of candidate mammalian taste receptors, T1 

receptors and T2 receptors, have been implicated in 

sweet, umami, and bitter detection. The T2 receptors 

are a group of �30 GPCRs that are specifically expressed 

in taste buds of the tongue and that are linked 

to bitter taste in mice and humans (6, 78, 94, 429). The 

T1 receptor family consists of only three GPCRs and 

has been shown to form heterodimers. T1R1 and T1R3 

form a receptor that responds to amino acids carrying 

the umami taste (477), and T1R2 forms heterodimers 

with T1R3 that functions as a sweet receptor (386, 477). 

Studies in knockout mice support a role of T1R2/T1R3 

as a sweet receptor and of T1R1/T1R3 as an umami 

receptor. In addition, T1R3 may form homodimers that 

can also mediate some sweet tastes, and there is evidence 

that also a splice variant of the mGluR4 glutamate 

receptor may be involved in umami sensation (95, 

96, 127, 730). The signal transduction mechanisms used 

by different G protein-coupled taste receptors are less 

clear. Gustducin, a G protein mainly expressed in taste 

cells, is believed to be able to couple receptors to 

phosphodiesterase resulting in a decrease of cyclic nucleotide 

levels. Mice lacking the �-subunit of gustducin 

show impaired responses to bitter, sweet, as well as 

umami tastes (247, 555, 692). However, the residual 

bitter and sweet taste responses in G� gust-deficient 

mice and the finding that expression of a dominant 

negative mutant of �-gustducin reduces this responsiveness 

even further indicates that �-gustducin is not 

the only �-subunit involved in sweet, bitter, and umami 

signal transduction (416, 556). In addition, �-gustducindeficient 

mice expressing the �-subunit of rod-transducin 

as a transgene driven by the �-gustducin promoter 

partially recovered responses to sweet and bitter compounds 

(247). However, in mice lacking the �-subunit 

of rod-transducin, responses to bitter and sweet compounds 

were normal, whereas the responses to various 

umami compounds were impaired (249). Thus gustducin 

is involved in sweet, bitter, and umami taste detection, 

whereas rod-transducin mediates part of umami 

taste sensation. Both gustducin and transducin are able 

to activate phosphodiesterase, thereby leading to decreased 

cGMP levels, disinhibition of cyclic nucleotideinhibited 

channels, and calcium influx. In addition, bitter 

tastants have also been shown to activate PLC-� 2 

through G�� subunits (probably G� 3� 13) released from 

gustducin or other G proteins (416), and PLC� 2 has 

recently been shown to be involved in the activation of 

transient receptor potential M5 (TRPM5) cation channels, 

which cause depolarization of the cells (729). 

Interestingly, mice lacking PLC-� 2 or TRPM5 are completely 

insensitive not only to bitter tastants but also to 

sweet and umami (729), indicating that the G protein/ 

PLC-� 2/TRPM5 signaling cascade is centrally involved 

in the sensation of these three taste qualities. However, 

other signal transduction pathways have been suggested, 

and it is not clear how gustducin or transducin 

functions are related to those of PLC� 2 and TRPM5. 

VII. DEVELOPMENT 


Although heterotrimeric G proteins are expressed 

throughout the prenatal development of the mammalian 

organism, only a limited number of studies have so far

addressed the role of G proteins in development. Most 

insights into the developmental role of G protein-mediated 

signaling pathways came from studies on mouse 

mutants lacking individual G protein �-subunits. Some 

null mutations like those of the genes encoding G� s,G� 13, 

or G� q/G� 11 are embryonic lethal (493, 495, 723) and 

clearly indicate an essential role during development. 

A. G 13-Mediated Signaling in 

Embryonic Angiogenesis 

Both G 12 and G 13 have been shown to induce cytoskeletal 

rearrangements in a Rho-dependent manner 

(79, 563). Lack of G� 13 in mice results in embryonic 

lethality at midgestation. At this stage, mouse embryos 

express both G� 12 and G� 13. G� 13-deficient mouse embryos 

show a defective organization of the vascular system, 

which is most prominent in the yolk sac and in the 

head mesenchyme (493). Vasculogenic blood vessel formation 

through the differentiation of progenitor cells into 

endothelial cells was not affected by the loss of G� 13. 

However, angiogenesis which includes sprouting, growth, 

migration, and remodeling of existing endothelial cells, 

was severely disturbed, and the maintenance of the integrity 

of newly developed vessels appeared to be defective 

in G� 13-deficient embryos. Chemokinetic effects of 

thrombin, which acts through protease-activated receptors 

(PARs), were completely abrogated in fibroblasts 

lacking G� 13, indicating that G� 13 is required for full 

migratory responses of cells to certain stimuli. Interestingly, 

approximately one-half of the embryos that lack the 

protease-activated receptor 1 (PAR-1) also die at midgestation 

with bleeding from multiple sites (118). This phenotype 

of embryos lacking PAR-1 which is expressed in 

endothelial cells, can be rescued by a PAR-1 transgene 

whose expression is driven by an endothelial-specific promoter 

(226). This clearly indicates that PAR-1 function is 

required for proper vascular development. The more severe 

embryonic defect of G� 13 compared with PAR-1deficient 

embryos suggests that G� 13 function is not restricted 

to protease-activated receptor signaling. 

The defects observed in G� 13-deficient embryos and 

cells occurred in the presence of G� 12, and loss of G� 12 

did not result in any obvious defects during development. 

Interestingly, G� 12-deficient mice that carry only one intact 

G� 13 allele also die in utero (228). This genetic evidence 

indicates that G� 13 and its closest relative, G� 12, fulfill at 

least partially nonoverlapping cellular and biologic functions, 

which are required for proper development. 

B. G q/G 11-Mediated Signaling During Embryonic 

Myocardial Growth 

The G� q/G� 11-mediated signaling pathway appears to 

play a pivotal role in the regulation of the physiological 


myocardial growth during embryogenesis. This is demonstrated 

by the phenotype of mice lacking both G� q and 

G� 11. These mice die at embryonic day 11 due to a severe 

thinning of the myocardial layer of the heart (495). Both 

the trabecular ventricular myocardium as well as the 

subepicardial layer appeared to be underdeveloped. 

There are several G q/G 11-coupled receptors that may be 

involved in the regulation of cardiac growth at midgestation. 

Inactivation of the gene encoding the G q/G 11-coupled 

serotonin 5-HT 2B receptors in mice resulted in cardiomyopathy 

with a loss of ventricular mass due to a reduction 

in the number and size of cardiomyocytes (473), and lack 

of both endothelin A (ET A) and endothelin B (ET B) receptors, 

which can signal through G q/G 11, resulted in 

midgestational cardiac failure (710). Most likely there is 

some degree of signaling redundancy with several inputs 

into the G q/G 11-mediated signaling pathway, and only deletion 

of both the G� q and the G� 11 gene results in severe 

phenotypic defects during early heart development. Interestingly, 

one intact allele of the G� q or the G� 11 gene was 

sufficient to overcome the early developmental block in 

heart development. However, newborn mice that have 

only one intact G� q or G� 11 allele show an increased 

incidence of cardiac defects ranging from septal defects 

to univentricular hearts (495). 

C. Neural Crest Development 


Signaling through G q/G 11 has been implicated in the 

proliferation and/or migration of neural crest cells. ET-1 

and the G q/G 11-coupled endothelin A (ET A) receptor are 

essential for normal function of craniofacial and cardiac 

neural crest. ET-1 and ET A receptor-deficient mice die 

shortly after birth due to respiratory failure (114, 357, 

358). Severe skeletal abnormalities could be observed in 

their craniofacial region, including a homeotic transformation 

of mandibular arch-derived structures into maxillary-like 

structures as well as absence of auditory ossicles 

and tympanic ring (503, 553). A hypomorphic phenotype 

similar to, but less severe than ET A or ET-1 null mice 

could be observed in G� q (�/�);G� 11 (�/�) mice (495). 

In G� q/G� 11 double-deficient mice studied at embryonic 

day 9.5, a expression of ET-1-dependent transcription 

factors like Dlx3, Dlx6, dHAND, and eHAND was ablated 

(297), a finding similar to those made in mice lacking ET A 

or ET-1 (114, 629). This suggests that in the neural crestderived 

pharyngeal arch mesenchyme, a signaling pathway 

involving ET-1, ET A receptors, and G� q/G� 11 is operating. 

ET-1, which is expressed in the pharyngeal 

endoderm binds to ET A receptors in neural crest cells of 

the pharyngeal archs of embryonic day 9.5 embryos 

(114). G q/G 11 then couples ET A receptors via phospholipase 

C-� activation to the activation of the expression of 

genes encoding transcription factors including Dlx3,


Dlx6, dHAND and eHAND (297). In contrast, G� q (�/�); 

G� 11 (�/�) mice did not show any craniofacial abnormalities 

indicating that ET A receptor-mediated neural crest 

development requires a certain amount of G� q/G� 11. Itis 

also possible that G� 11 is expressed at lower levels than 

G� q in the neural crest-derived mesenchyme of the pharyngeal 

archs, or that the ET A receptor couples preferentially 

to G� q. 

The ET-3 and ET B receptor system has been shown 

to be involved in the development of neural crest cells 

taking part in the formation of epidermal melanocytes as 

well as the myenteric ganglia of the distal colon. In mice 

lacking ET-3 or the ET B receptor, this results in whitespotted 

hair and skin color as well as a dilation of the 

proximal colon (38, 710). These defects are very similar to 

those present in humans suffering from multigenic 

Hirschsprung disease, which in various cases has been 

shown to be caused by mutations in ET B or ET-3 genes 

(158, 204). Whether G q/G 11-mediated signaling is involved 

in ET-3-induced differentiation of cutaneous and enteric 

neural crest cells has not been studied directly so far. 

However, several hypermorphic alleles of the G� q and 

G� 11 genes have recently been found in mouse mutants 

with an aberrant accumulation of pigment-producing melanocytes 

(302, 642). Genetic evidence was provided that 

the action of G� q/G� 11 depended on the ET B receptor. 

VIII. CELL GROWTH AND TRANSFORMATION 

During recent years it has become obvious that 

GPCRs and heterotrimeric G proteins play important 

roles in the regulation of cell growth and that some G 

proteins can induce cellular transformation (140, 229, 

549). Many G protein �-subunits are able to transform 

cells under certain conditions when rendered constitutively 

active by inducing GTPase inactivating mutations. 

In some cases, activated G protein �-subunits have been 

found in human tumors. 

A. Constitutively Active Mutants of G� q/G� 11 

Family Members 

Transforming mutants of G� q/G� 11 have not been 

found in human tumors. However, their potential oncogenic 

function has been studied in cell lines by expression 

of constitutively active forms like G� qQ209L or 

G� 11Q209L. These studies indicated that activated G� q/11 

can lead to transformation of fibroblasts when expressed 

at low levels (318) but induces growth inhibition and 

apoptosis when expressed at higher levels (140). Interestingly, 

various G q/G 11-coupled receptors have been shown 

to possess highly transforming activity. This has very 

early been shown for the 5-HT 2C serotonin receptor as 

well as for the M 1, M 3, and M 5 muscarinic receptors, 


which are able to transform fibroblasts in the presence of 

a receptor agonist (231, 315). It is well known that various 

G q/G 11-coupled neuropeptide receptors like those for gastrin-releasing 

peptides, galanin, neuromedin B, vasopressin, 

and others are involved in the autocrine and paracrine 

stimulation of proliferation in small cell lung cancer cells 

(250). This suggests that endogenous G q/G 11-coupled receptors 

can be tumorigenic in the presence of excess 

ligands. In vitro experiments indicate that constitutively 

active G q/G 11-coupled receptors can enhance mitogenesis 

and tumorigenicity (14), and the virally encoded KSHV-G 

protein-coupled receptor, which is a constitutively active 

G q/G 11-coupled receptor, has been shown to behave as a 

viral oncogene and angiogenesis activator and appears to 

be involved in Kaposi sarcoma progression (26, 29, 458). 

B. The Oncogenic Potential of G� s 

G s-mediated increases in cAMP can induce growth 

inhibition in some tissues while in others it can have a 

transforming potential. The gsp oncogene encodes a 

GTPase-deficient mutant of G� s and has been found in up 

to 30% of thyroid toxic adenomas and in a few thyroid 

carcinomas. A constitutively active mutant of G� s has 

also been found in GH-secreting pituitary adenomas as 

well as in the McCune-Albright syndrome (172, 599). Interestingly, 

responses to constitutively active G� s are cell 

type specific. In some cells, an increase in cAMP and 

consecutive activation of PKA can inhibit Raf kinase and 

prevent transformation of cells (102). In contrast, in various 

neuronal and neuroendocrine cells, G� s-mediated 

cAMP formation activates cell growth (164, 551). The 

transforming potential of G s obviously depends on the 

cellular context that links G s-mediated cAMP formation 

to inhibition or stimulation of ERK (604). While various 

kinases upstream of ERK have been involved in cAMP/ 

PKA-induced ERK regulation, the determinants of the net 

proliferative effect of cAMP remain elusive (604). A proposed 

role of the cAMP-activated Epac/Rap1 pathway in 

cAMP-mediated ERK activation has been questioned 

(163). 

The potential of G s-mediated signaling to induce tumor 

formation in endocrine cells is also underlined by the 

fact that constitutively active mutants of various G s-coupled 

receptors have been detected in human tumors. Up 

to 80% of hyperfunctioning human thyroid adenomas and 

a minority of differentiated thyroid carcinomas have been 

shown to contain constitutively active TSH receptors 

(507, 508). Similarly, mutations resulting in constitutive 

activation of the luteinizing hormone receptor have been 

shown to cause hyperplastic growth of Leydig cells in a 

form of familial male precautious puberty (578) as well as 

in Leydig cell tumors (393).

C. G i-Mediated Cell Transformation 

The gip2 oncogene that encodes an active mutant of 

G� i2 has been found in adrenal cortical tumors as well as 

in human ovarian sex cord stromal tumors (406). It is a 

matter of debate how frequent these G� i2 mutations occur 

in these tumors. Expression of constitutively active G� i2 

in fibroblast cell lines leads to cell transformation, an 

effect which has not been completely understood yet, but 

may result from the derepression of the Ras/ERK pathway 

in response to a decrease in cellular cAMP levels (446, 

640). Depending on the cellular system, G i-mediated release 

of free ��-subunits may also be involved in the 

growth-promoting effect of G� i2 (122). 

D. Cellular Growth Induced by G� 12/G� 13 

The G protein �-subunit G� 12 was identified as an 

oncogene present in soft tissue sarcoma (93). This oncogene, 

termed gep, encoded the wild-type form of G� 12. At 

the same time, the potent transforming ability of constitutively 

active mutants of G� 12 and G� 13 could be shown 

in various systems (307, 645, 655, 703, 704). While no 

activating mutation of G� 12 or G� 13 has been found in 

human tumors, increased expression levels of both proteins 

have been detected in various human cancers (230). 

Both G� 12 and G� 13 can induce activation of the small 

GTPase RhoA via regulation of a subgroup of RhoGEF 

proteins (195, 236). Interestingly, RhoA has been found to 

be overexpressed in various tumor types (2, 192, 320), and 

Rho GTPases have been involved in carcinogenesis and 

cancer progression (385, 564). Recently, an interesting 

link between G 12/G 13- and cadherin-mediated signaling 

was described (327, 434, 435). Active G� 12 and G� 13 can 

interact with the cytoplasmic domain of some type I and 

type II class cadherins, like E-cadherin, N-cadherin, or 

cadherin-14, causing the release of �-catenin from cadherins 

and its relocalization to the cytoplasm and nucleus, 

where it is involved in transcriptional activation. In addition, 

activated G� 12 can block cadherin-mediated cell adhesion 

in various cells including breast cancer cells (434). 

This downregulation of cadherin-mediated cell adhesion 

and the release of �-catenin from cadherins may be a 

mechanism by which G� 12/G� 13 induces cellular transformation 

and metastatic tumor progression. 

IX. CONCLUDING REMARKS 

The field of heterotrimeric G proteins was launched 

more than 30 years ago when the involvement of guanine 

nucleotides in the hormonal stimulation of adenylyl cyclase 

was discovered. Since then, the field has enormously 

expanded, and G protein-mediated signal transduction 

has turned out to be the most widely used trans- 


membrane signaling system in higher organisms. It 

consists of hundreds of receptors that signal to dozens of 

G proteins and effectors. The modular nature of this 

signal transduction system with multiple components enables 

cells to assemble vast, combinatorially complex 

signaling units that allow different cells in different contexts 

to respond adequately to extracellular signals. There 

is probably not a single cell in a mammalian organism that 

does not employ several G protein-mediated signaling 

pathways. Often these pathways integrate the information 

conveyed by several receptors recognizing different ligands. 

Only in recent years did we gain a more systematic 

insight into the role of individual G proteins on a cellular 

and supracellular level. However, many aspects of G protein-mediated 

signaling, especially under in vivo conditions, 

still remain to be elucidated. While many components 

of the system have been identified, new approaches 

are required to determine the exact composition of individual 

signaling units and to define their exact cellular 

localization. This will probably lead to the identification 

of even more proteins and nonprotein factors that modulate 

G protein-mediated signaling. An increasing use of 

in vivo models is necessary to test the significance of 

signaling mechanisms described in vitro under normal 

conditions as well as in disease states. The parallel application 

of genetic, genomic, and of new proteomic approaches 

will be required to continue to define how the G 

protein-mediated signaling system works on a molecular, 

cellular, and systemic level. Such an integrated view will 

provide the basis for a full understanding of the physiological 

and pathophysiological role of G protein-mediated 

signaling and will allow the full exploitation of this multifaceted 

signaling system as a target for pharmacological 

interventions. 

ACKNOWLEDGMENTS 

Address for reprint requests and other correspondence: S. 

Offermanns, Institute of Pharmacology, Univ. of Heidelberg, Im 

Neuenheimer Feld 366, D-69120 Heidelberg, Germany (E-mail: 

stefan.offermanns@urz.uni-heidelberg.de). 

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