section 30.5
Types of Hormone Receptors
717
Activation of Adenylate Cyclase
t
G
Sa-GTP
F IG U R E 3 0 -7
Activation and inactivation (or return to resting state) of signal transducer trimeric stimulatory G-protein (Gs). Hormone
binding to membrane G-protein-coupled stimulatory receptor causes a GTP and GDP exchange reaction in Gsa and
dissociation of
Gpy .
Gs<
i .gtp activates adenylate cyclase and initiates the signal transduction pathway. The return of
Gsa.gtp to the resting state is mediated by the intrinsic GTPase activity of the Gsa subunit and also through promotion of
GTPase activity by the RGS protein. Activation of Gj protein occurs by analogous reactions of Gs when a hormone binds
to its corresponding inhibitory receptor. This leads to the formation of Gja.GTP which inhibits adenylate cyclase. Gain in
function or loss in function can result from mutations in genes coding for receptor protein, Gsa, Gia, or RGS protein.
relative rates of cAMP synthesis by adenylate cyclase and
of degradation by phosphodiesterase, is elevated above
basal levels. The reaction catalyzed by the phosphodies-
terase is
3\5'-cAMP + H20
5'-AMP
As cAMP concentration decreases, reassociation of cat-
alytic and regulatory subunits of the kinase occurs.
The cAMP system also derives some of its specificity
from the proteins that are substrates for cAMP-dependent
protein kinase. It is an indirect regulatory system, since
cAMP modulates the activity of cAMP-dependent pro-
tein kinase and the kinase, in turn, affects the activi-
ties of a variety of metabolic enzymes or other proteins.
This indirectness is the basis for amplification of the hor-
monal signal. Activation of adenylate cyclase by binding
of a hormone molecule to a receptor causes formation of
many molecules of cAMP and allows activation of many
molecules of the protein kinase, each of which in turn
can phosphorylate many enzymes or other proteins. This
“amplification cascade” accounts in part for the extreme
sensitivity of metabolic responses to small changes in hor-
mone concentrations. Finally, the response to increased
cAMP concentrations within a cell usually involves sev-
eral metabolic pathways and a variety of enzymes or other
proteins.
Abnormalities in Initiation of G-Protein Signal
Two-well studied bacterial toxins, cholera toxin and per-
tussis toxin, perturb normal functioning of G„ proteins
by ADP ribosylation of specific amino acid residues (dis-
cussed earlier).
Germline and somatic mutations in the genes coding for
G-proteins can cause endocrine disorders in several ways.
Mutations can be either activating (gain of function) or in-
activating (loss of function). Examples of gain-in-function
mutations that result in the ligand-independent activator
of Gso, include some adenomas of pituitary and thyroid,
some adenomas of adrenals and ovary, and syndromes of
hyperfunction of one or more endocrine glands. In most
of these disorders, a point mutation alters an amino acid
in Gs„ leading to inhibition of GTP hydrolysis required
for the termination of the activity of Gs„. An example of
autonomous hyperhormone secretion and cellular prolif-
eration of several endocrine glands is
McCune-Albright
syndrome.
In this disorder, two missense mutations re-
sult in the replacement of Arg
2 0 1
-* His or Arg
2 0 1
—>
Cy in Gs„ of affected endocrine glands. Some of the clini-
cal manifestations of McCune-Albright syndrome include
hyperthyroidism, polyostotic fibrous dysplasia, and hy-
perpigmented irregularly shaped skin lesions (known as
café-au-lait lesions
). The cutaneous hyperpigmentation
