section 30.5
Types of Hormone Receptors
Stimulatory Receptor (Rs)
Inhibitory Receptor (R.)
Dual control of adenylate cyclase activity by guanine nucleotide-binding proteins (G). Subscripts s and i denote
stimulatory and inhibitory species, respectively. + and —
indicate activation and inactivation, respectively.
(RGS) proteins, which bind to G„ and promote GTPase
activity. This process of converting G„ from an active state
to an inactive state is rapid. Transcriptional regulation and
posttranslational modification of G-proteins provide other
means for regulation of the G-protein-coupled signaling
Understanding of G-proteins has been aided by spe-
cific agents that modify Gs or G; and by mutant mouse
lymphoma cell lines deficient in Gs activity. Both Gs„
contain sites for NAD+-dependent ADP ribosy-
lation. Cholera toxin ADP-ribosylates a specific arginine
side chain of Gs„ and maintains it in a permanently ac-
tive state, while islet-activating protein, one of the toxins
Bordetella pertussis,
ADP-ribosylates a specific cys-
teine side chain of G;„, permanently blocking its inhibitory
action because it maintains
in the GDP form. Thus,
both toxins stimulate adenylate cyclase activity and lead
to excessive production of cAMP. Cholera toxin causes a
diarrheal illness (Chapter 12), while toxins of
B. pertus-
cause whooping cough, a respiratory disease affecting
ciliated bronchial epithelium.
Response of the adenylate cyclase system to a hormone
is determined by the types and amounts of various con-
stituent proteins. Cyclic AMP production is limited by the
amount of adenylate cyclase present. When all the adeny-
late cyclase is fully stimulated, further hormone binding
to Rs’s cannot increase the rate of cAMP synthesis. In
cells having many different Rs’s (adipocytes have them
for epinephrine, ACTH, TSH, glucagon, MSH, and va-
sopressin), maximal occupancy of the receptors may not
stimulate cAMP production beyond what can be achieved
by full occupancy of only a few of the receptor types.
Therefore, the greatest stimulation that can be achieved
by a combination of several hormones will not be simply
the sum of the maximal effects of the same hormones given
singly. A hormone’s ability to stimulate cAMP production
may depend on the cell type. For example, epinephrine
causes large increases in cAMP concentration in muscle
but has relatively little effect on liver. The opposite is true
for glucagon (see Chapter 15). Within a particular cell
type, destruction of one type of Rs does not alter the re-
sponse of the cell to hormones that bind other stimulatory
In prokaryotic cells, cAMP binds to catabolite regula-
tory protein (CAP), which then binds to DNA and affects
gene expression (Chapter 26). In eukaryotic cells, cAMP
binds to cAMP-dependent protein kinase, which contains
two regulatory (R) and two catalytic (C) subunits. Upon
binding of cAMP, the catalytic subunits separate, become
+ 4cAMP ^ 2(R-2cAMP) + 2C
and catalyze ATP-dependent phosphorylation of serine
and threonine residues of various cell proteins, often al-
tering the activities of these proteins. Some, such as
phosphorylase kinase, become activated, whereas others,
such as glycogen synthase, are inactivated (Chapter 15).
Cyclic AMP-dependent protein kinase remains active
while intracellular cAMP concentration, controlled by the
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