Essential Cell Biology 5th edition

G-Protein-Coupled Receptors
545
Whereas ion-channel-coupled receptors are especially important in
nerve cells and other electrically excitable cells such as muscle cells,
G-protein-coupled receptors and enzyme-coupled receptors are important
for practically every cell type in the body. Most of the remainder of
this chapter deals with these two receptor families and with the signal
transduction processes that they use.
G-PROTEIN-COUPLED RECEPTORS
G-protein-coupled receptors (GPCRs) form the largest family of cellsurface
receptors. There are more than 700 GPCRs in humans, and mice
have about 1000 involved in the sense of smell alone. These receptors
mediate responses to an enormous diversity of extracellular signal molecules,
including hormones, local mediators, and neurotransmitters. The
signal molecules that bind GPCRs are as varied in structure as they are
in function: they can be proteins, small peptides, or derivatives of amino
acids or fatty acids, and for each one of them there is a different receptor
or set of receptors. Because GPCRs are involved in such a large variety of
cell processes, they are an attractive target for the development of drugs
to treat many disorders. About one-third of all drugs used today work
through GPCRs.
Despite the diversity of the signal molecules that bind to them, all GPCRs
have a similar structure: each is made of a single polypeptide chain that
threads back and forth across the lipid bilayer seven times (Figure 16–14).
The GPCR superfamily includes rhodopsin (the light-activated photoreceptor
protein in the vertebrate eye), the olfactory (smell) receptors in the
vertebrate nose, and the receptors that participate in the mating rituals
of single-celled yeasts (see Figure 16–1). Evolutionarily speaking, GPCRs
are ancient: even prokaryotes possess structurally similar membrane
proteins—such as the bacteriorhodopsin that functions as a light-driven
H + pump (see Figure 11−28). Although they resemble eukaryotic GPCRs,
these prokaryotic proteins do not act through G proteins, but are coupled
to other signal transduction systems.
We begin this section with a discussion of how G proteins are activated
by GPCRs. We then consider how activated G proteins stimulate ion
channels and how they regulate membrane-bound enzymes that control
the concentrations of small intracellular messenger molecules, including
cyclic AMP and Ca 2+ , which in turn control the activity of important
intracellular signaling proteins. We end with a discussion of how lightactivated
GPCRs in photoreceptors in our eyes enable us to see.
Stimulation of GPCRs Activates G-Protein Subunits
(A)
(B)
plasma
membrane
EXTRACELLULAR
SPACE
CYTOSOL
Figure 16–14 All GPCRs possess a similar
structure. The polypeptide chain traverses
the membrane as seven α helices. The
cytoplasmic portions of the receptor bind to
a G protein inside the cell. (A) For receptors
that recognize small signal molecules, such
as acetylcholine or epinephrine, the ligand
(red) usually ECB5 e16.18-18.14
binds deep within the plane of
the membrane to a pocket that is formed
by amino acids from several transmembrane
segments. Receptors that recognize signal
molecules that are proteins usually have a
large, extracellular domain that, together
with some of the transmembrane segments,
binds the protein ligand (not shown).
(B) Shown here is the structure of a GPCR
that binds to epinephrine (red ). Stimulation
of this receptor by epinephrine makes the
heart beat faster.
When an extracellular signal molecule binds to a GPCR, the receptor
protein undergoes a conformational change that enables it to activate a
G protein located on the other side of the plasma membrane. To explain
how this activation leads to the transmission of a signal, we must first
consider how G proteins are constructed and how they operate.
There are several varieties of G proteins. Each is specific for a particular
set of receptors and for a particular set of target enzymes or ion channels
in the plasma membrane. All of these G proteins, however, have a similar
general structure and operate in a similar way. They are composed
of three protein subunits—α, β, and γ—two of which are tethered to the
plasma membrane by short lipid tails. In the unstimulated state, the α
subunit has GDP bound to it, and the G protein is idle (Figure 16–15A).
When an extracellular signal molecule binds to its receptor, the altered
receptor activates a G protein by causing the α subunit to decrease its