Activation of all three receptor subtypes (β1, β2, and β3) results in stimulation of adenylyl cyclase and increased cAMP (Table 9–1,
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, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated αi 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 cAMPdependent 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 α2 adrenoceptors.
Figure 9–2). Activation of the cyclase enzyme is mediated by the stimulatory coupling protein Gs. Cyclic AMP is the major second messenger of β-receptor activation. For example, in the liver of many species, β-receptor–activated cAMP synthesis leads to a cascade of events culminating in the activation of glycogen phosphorylase. In the heart, β-receptor–activated cAMP synthesis increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. Although the mechanism of the smooth muscle effect is uncertain, it may involve the phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium channels in the heart via coupling to Gs but independent of cAMP. Under certain circumstances, β2 receptors may couple to Gq proteins. These receptors have been demonstrated to activate additional kinases, such as MAP kinases, by forming multi-subunit complexes containing multiple signaling molecules.
The β3 adrenoreceptor is a lower affinity receptor compared with β1 and β2 receptors but is more resistant to desensitization. It is found in several tissues, but its physiologic or pathologic role in humans is not clear. β3 receptors are expressed in the detrusor muscle of the bladder and induce its relaxation. Mirabegron, a selective β3 agonist, is approved for the treatment of symptoms of overactive bladder (urinary urgency and frequency). A small increase in blood pressure was observed in clinical trials; the longterm significance of this finding is not clear.
C. Dopamine Receptors
The D1 receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D1-receptor–induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.
TABLE 9–2 Relative receptor affinities.
1See text.