section 30.5

Types of Hormone Receptors

715

Stimulatory Receptor (Rs)

Inhibitory Receptor (R.)

FIGURE 30-5

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

pathway.

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„

and

Glo

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

in

Bordetella pertussis,

ADP-ribosylates a specific cys-

teine side chain of G;„, permanently blocking its inhibitory

action because it maintains

GUJ

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-

sis

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

receptors.

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

active,

R

2

C

2

+ 4cAMP ^ 2(R-2cAMP) + 2C

(inactive)

(active)

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