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