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140 SECTION II Autonomic Drugs

Agonist Agonist

G S Adenylyl G i
cyclase

{
βγ G S {
β
γ
α S α * + – α * i α i
S
Beta GTP GDP
receptor GDP GTP Alpha 2
receptor
GTP GDP GDP GTP

ATP cAMP
Enzyme +

ATP
+ 2C R C 2 protein kinase
2
ADP

Enzyme-PO 4 2R

Biologic effect

FIGURE 9–2 Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors
stimulates adenylyl cyclase by activating the stimulatory G protein, G s , which leads to the dissociation of its α subunit charged with GTP. This
activated α s subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha 2 -adrenoceptor ligands inhibit
adenylyl cyclase by causing dissociation of the inhibitory G protein, G i , into its subunits; ie, an activated α i subunit charged with GTP and a
β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-
dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify
their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See
text for other actions of β and α 2 adrenoceptors.

Figure 9–2). Activation of the cyclase enzyme is mediated by The β adrenoreceptor is a lower affinity receptor compared
3
the stimulatory coupling protein G . Cyclic AMP is the major with β and β receptors but is more resistant to desensitization.
s
2
1
second messenger of β-receptor activation. For example, in the It is found in several tissues, but its physiologic or pathologic role
liver of many species, β-receptor–activated cAMP synthesis leads in humans is not clear. β 3 receptors are expressed in the detrusor
to a cascade of events culminating in the activation of glycogen muscle of the bladder and induce its relaxation. Mirabegron, a
phosphorylase. In the heart, β-receptor–activated cAMP syn- selective β agonist, is approved for the treatment of symptoms
3
thesis increases the influx of calcium across the cell membrane of overactive bladder (urinary urgency and frequency). A small
and its sequestration inside the cell. Beta-receptor activation increase in blood pressure was observed in clinical trials; the long-
also promotes the relaxation of smooth muscle. Although the term significance of this finding is not clear.
mechanism of the smooth muscle effect is uncertain, it may
involve the phosphorylation of myosin light-chain kinase to an C. Dopamine Receptors
inactive form (see Figure 12–1). Beta adrenoceptors may acti- The D receptor is typically associated with the stimulation of
1
vate voltage-sensitive calcium channels in the heart via coupling adenylyl cyclase (Table 9–1); for example, D -receptor–induced
1
but independent of cAMP. Under certain circumstances, smooth muscle relaxation is presumably due to cAMP accumula-
to G s
β receptors may couple to G proteins. These receptors have tion in the smooth muscle of those vascular beds in which dopa-
2
q
been demonstrated to activate additional kinases, such as MAP mine is a vasodilator. D receptors have been found to inhibit
2
kinases, by forming multi-subunit complexes containing multiple adenylyl cyclase activity, open potassium channels, and decrease
signaling molecules. calcium influx.