section 30.5
Types of Hormone Receptors
713
number of steroid-regulated genes are subject to modu-
lation by CREB and are thus subject to the regulatory
influence of both steroid and peptide hormones.
Cell Surface Receptors
Many hormones, such as the hormonal amines and all pep-
tidic hormones, are unable to penetrate the lipid matrix of
the cell membrane, and thus depend on the presence of
receptor sites at the surface of target cells. As listed in
Table 30-4, there are several types of cell membrane re-
ceptors for these hormones, each of which is coupled to a
distinct set of intracellular postreceptor pathways. The sur-
face receptors all initiate postreceptor events that involve
the phosphorylation of one or more intracellular proteins,
some of which are enzymes whose activities depend on the
state of phosphorylation. In two of these cases, an intracel-
lular second messenger is utilized to implement the hor-
monal action and involves G-protein-coupled receptors.
One is coupled to the adenylate cyclase-cAMP system and
the other is associated with the phosphatidylinositol-Ca2+
pathway (IP
3
pathway).
G-Protein-Coupled Adenylate
Cyclase-cAMP System
The effect on adenylate cyclase of ligand binding to spe-
cific receptors mediated by heterotrimeric G-proteins is
shown in Figure 30-5. The G-proteins belong to a family
of regulatory proteins each of which regulates a distinct
set of signaling pathways. The cell membrane receptors
coupled to intracellular G-proteins share a common seven
transmembrane-spanning a-helical serpentine structure;
however, they do not show a common overall sequence
homology. The a-helical segments are linked with alter-
nating intracellular and extracellular peptide loops with
the N-terminal region located on the extracellular side and
C-terminal region located on the intracellular side (Figure
30-6). Receptors coupled to G-proteins have been divided
into three subfamilies and significant sequence homolo-
gies do exist within the families, the receptors belonging
to the three families are described in Figure 30-6.
Extracellular signals detected by the membrane re-
ceptors are diverse and include hormones, growth fac-
tors, neurotransmitters, odorants, and light. Examples
of G-proteins are Gs, G;, products of
ras
oncogenes
(Chapter 26), and transducin. Transducin is a constituent of
the light-activated cGMP-phosphodiesterase system in the
retina (Chapter 38). This system is similar to the adenylate
cyclase system except that light is the ligand, rhodopsin
is the membrane receptor, cGMP-phosphodiesterase is the
effector, and the G-protein is the transducer. The two types
of receptors, Rs and Ri, can be functionally linked to
adenylate cyclase (Figure 30-5). Binding of an appropri-
ate ligand to Rs stimulates the adenylate cyclase whereas
binding to Rj inhibits the enzyme. The G-proteins are
heterotrimeric consisting of an a subunit and a tightly
coupled y8
y
subunit. The
a
subunit is the unique protein
in the trimer. It possesses sites for interaction with cell
membrane receptors,
fiy
subunit, intrinsic GTPase activ-
ity, and ADP ribosylation. In the unstimulated state, the
G-protein is present in the heterotrimeric
(afiy)
form with
GDP tightly bound to the
a
subunit. Upon activation of the
receptor by the bound ligand, GDP is exchanged for GTP
on the
a
subunit followed by dissociation of Gsa!GTP from
the /3
y
subunit. The
a
subunits Gs and G; are designated
Gs„ and G,„. The G-protein subunits undergo posttransla-
tional covalent additions of lipids such as palmitoyl, farne-
syl, and geranyl groups. These hydrophobic groups linked
to G-protein subunits are necessary for proper anchoring
in the cell membrane.
Figure 30-7 shows the cyclic functioning of the Gs pro-
tein. Binding of a hormone to Rs permits binding of GTP
to
Gsu
to form a Gs„.gtp complex and release of the G
p
and
Gy subunits. The Gsq
.,gtp complex activates adenylate cy-
clase which remains active as long as GTP is bound to Gs„.
Binding of GTP to Gs„ also activates a GTPase intrinsic to
Gsa that slowly hydrolyzes the bound GTP (GTP turnover
is one per minute), eventually allowing reassociation and
formation of the trimer and inactivation of adenylate cy-
clase. A similar series of events is initiated by binding
of a ligand to R;. In this instance, dissociation of the Gj
trimer by formation of Gj&
.oTp inhibits adenylate cyclase
and may allow the
f},y
subunit to bind to Gsct, preventing
Gsa! from activating adenylate cyclase. GTP hydrolysis by
GTP-activated GK
,-GTPase allows re-formation of the G;
trimer. GDP is displaced from
G,a
by binding of another
molecule of GTP with reactivation of
Gia.
The inhibitory
effect occurs because the target cell contains much more
G; than Gs.
Glu
may also interact with membrane calcium
transport and the phosphatidylinositol pathway. The func-
tion of
j3y
dimers is not completely understood but they
may participate in the regulation of downstream effectors
in the signaling pathway.
The G-protein-coupled receptor signaling pathway is
regulated by several different mechanisms. Negative reg-
ulation of the signaling pathway can occur at both the
receptor and G-protein levels. Receptor phosphorylation
by G-protein-coupled receptor kinase and arrestin bind-
ing can lead to inability of the ligand to activate the signa-
ling system (e.g., /1-adrenergic receptor-G-protein trans-
ducing system). Negative regulation also occurs after the
activation of G-protein, by promoting the GTPase activity
of
Gmuj
. This is achieved by regulator of G-protein signaling
