Ganong's Review of Medical Physiology, 23rd Edition

56 SECTION ICellular & Molecular Basis of Medical Physiology

CYCLIC AMP

Another important second messenger is cyclic adenosine 3',5'-
monophosphate (cyclic AMP or cAMP; Figure 2–27). Cyclic
AMP is formed from ATP by the action of the enzyme aden-
ylyl cyclase and converted to physiologically inactive 5'AMP
by the action of the enzyme phosphodiesterase. Some of the
phosphodiesterase isoforms that break down cAMP are inhib-
ited by methylxanthines such as caffeine and theophylline.
Consequently, these compounds can augment hormonal and
transmitter effects mediated via cAMP. Cyclic AMP activates
one of the cyclic nucleotide-dependent protein kinases (pro-
tein kinase A, PKA) that, like protein kinase C, catalyzes the
phosphorylation of proteins, changing their conformation
and altering their activity. In addition, the active catalytic sub-
unit of PKA moves to the nucleus and phosphorylates the
cAMP-responsive element-binding protein (CREB). This
transcription factor then binds to DNA and alters transcrip-
tion of a number of genes.

PRODUCTION OF cAMP

BY ADENLYL CYCLASE

Adenylyl cyclase is a transmembrane protein, and it crosses
the membrane 12 times. Ten isoforms of this enzyme have
been described and each can have distinct regulatory proper-
ties, permitting the cAMP pathway to be customized to specif-
ic tissue needs. Notably, stimulatory heterotrimeric G proteins
(Gs) activate, while inhibitory heterotrimeric G proteins (Gi)
inactivate adenylyl cyclase (Figure 2–28). When the appropri-
ate ligand binds to a stimulatory receptor, a Gs α subunit acti-
vates one of the adenylyl cyclases. Conversely, when the

appropriate ligand binds to an inhibitory receptor, a Gi α sub-

unit inhibits adenylyl cyclase. The receptors are specific, re-

sponding at low threshold to only one or a select group of

related ligands. However, heterotrimeric G proteins mediate

the stimulatory and inhibitory effects produced by many dif-

ferent ligands. In addition, cross-talk occurs between the

phospholipase C system and the adenylyl cyclase system, as

several of the isoforms of adenylyl cyclase are stimulated by

calmodulin. Finally, the effects of protein kinase A and protein

kinase C are very widespread and can also affect directly, or in-

directly, the activity at adenylyl cyclase. The close relationship

between activation of G proteins and adenylyl cyclases also al-

lows for spatial regulation of cAMP production. All of these

events, and others, allow for fine-tuning the cAMP response

for a particular physiological outcome in the cell.

Two bacterial toxins have important effects on adenylyl

cyclase that are mediated by G proteins. The A subunit of

cholera toxin catalyzes the transfer of ADP ribose to an argi-

nine residue in the middle of the α subunit of Gs. This inhibits

FIGURE 2–26 Diagrammatic representation of release of
inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as second
messengers. Binding of ligand to G protein-coupled receptor acti-
vates phospholipase C (PLC)β. Alternatively, activation of receptors
with intracellular tyrosine kinase domains can activate PLCγ. The re-
sulting hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP 2 ) pro-
duces IP 3 , which releases Ca2+ from the endoplasmic reticulum (ER),
and DAG, which activates protein kinase C (PKC). CaBP, Ca2+-binding
proteins. ISF, interstitial fluid.

Stimulatory

receptor

Tyrosine

kinase

Gq, etc

ISF

Phosphoproteins

Physiologic

ER effects

Cytoplasm

CaBP Ca^2 +

Physiologic effects

IP 3

PLC

PIP 2 DAG

PKC

α

β

γ

FIGURE 2–27 Formation and metabolism of cAMP. The sec-

ond messenger cAMP is a made from ATP by adenylyl cyclase and bro-

ken down into cAMP by phosphodiesterase.

OH

HO

H H

OH

O

P

O

P

O

P

O

OOO

HH

OH OH OH

CH 2 Adenine

OH

H H

OH

O

P

O

HO O

HH

OH

CH 2 Adenine

OH

OH

H H

O

O

O

O

HH

CH 2

P

Adenine

ATP

AMP

PP

cAMP

H 2 O

Phosphodiesterase

Adenylyl cyclase