Nina Wettschureck and Stefan Offermanns - Physiological Reviews

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1164 NINA WETTSCHURECK AND STEFAN OFFERMANNS 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 �7 GNG7 Widely �8, �9 GNG8 Olfactory/vomeronasal epithelium �10 GNG10 Widely �11 GNG11 Widely �12 GNG12 Widely �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 Physiol Rev • VOL 85 • OCTOBER 2005 • www.prv.org 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- CELLULAR FUNCTIONS OF G PROTEINS 1165 Physiol Rev • VOL 85 • OCTOBER 2005 • www.prv.org 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-
Page 1 and 2: Mammalian G Proteins and Their Cell
Page 3 and 4: TABLE 1. Physiological ligands of G
Page 5: TABLE 1—Continued Sensory Stimuli
Page 9 and 10: promoter driving the expression of
Page 11 and 12: FIG. 5.G q/G 11 family G proteins a
Page 13 and 14: G proteins, which mediate bronchoco
Page 15 and 16: lets under physiological and pathol
Page 17 and 18: to mediate these effects. The forme
Page 19 and 20: e attributed to an impaired lipolyt
Page 21 and 22: kocytes (56). Indirect evidence for
Page 23 and 24: A. Visual System The human retina c
Page 25 and 26: addressed the role of G proteins in
Page 27 and 28: C. G i-Mediated Cell Transformation
Page 29 and 30: 45. Berstein G, Blank JL, Jhon DY,
Page 31 and 32: 123. Cyster JG. Chemokines, sphingo
Page 33 and 34: 207. Gehrmann J, Meister M, Maguire
Page 35 and 36: 290. Imamura T, Vollenweider P, Ega
Page 37 and 38: 369. Laurent E, Mockel J, Van Sande
Page 39 and 40: Local calcium release in dendritic
Page 41 and 42: 533. Radu CG, Yang LV, Riedinger M,
Page 43 and 44: 616. Suwazono Y, Okubo Y, Kobayashi
Page 45 and 46: 695. Wu D, Huang CK, and Jiang H. R

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