G

Figure 16.6 • Mechanism of a-i-receptor-mediated signal transduction.

receptors that are linked to stimulation of biochemical processes in the postsynaptic cell. The function of presynaptic jS-receptors is, however, unclear. The jS-adrenoceptor subtypes also differ in terms of the rank order of potency of the adrenergic receptor agonists NE, E, and ISO (Table 16.4).

The use of jS2-agonists as bronchodilators and jS 1- or Si/S2-blockers as antihypertensives is well established. The ^-receptors are located mainly in the heart, where they mediate the positive inotropic and chronotropic effects of the CAs. They are also found on the juxtaglomerular cells of the kidney, where they are involved in increasing renin secretion. The jS2-receptors are located on smooth muscle throughout the body, where they are involved in relaxation of the smooth muscle, producing such effects as bronchodi-lation and vasodilation. They are also found in the liver, where they promote glycogenolysis. The jS3-receptor is located on brown adipose tissue and is involved in the stimulation of lipolysis.

All three jS-receptors are coupled to AC, which catalyzes the conversion of ATP to cAMP (Fig. 16.7). This coupling is via the G-protein Gs.25,26 In the absence of an agonist, guanosine diphosphate (GDP) is bound reversibly to the Gs protein. Interaction of the agonist with the receptor causes a conformational change in the receptor, which decreases the affinity of the Gs protein for GDP and a concomitantly increases the affinity for guanosine triphosphate (GTP). The as-subunit of Gs-protein complex dissociates from the re-ceptor-G protein tertiary complex and then binds to and activates AC.

The intracellular function of the second-messenger cAMP is activation of protein kinases, which phosphorylate specific proteins, thereby altering their function.27 The action of cAMP is terminated by a class of enzymes known as phosphodiesterase (PDE) that catalyzes the hydrolysis of cAMP to AMP (Fig. 16.7) and is related to the mechanism of action of caffeine and theophylline.

Cloning of the gene and complementary DNA (cDNA) for the mammalian jS-receptor has made it possible to explore the structure-function relationships of the receptor.28 Through such studies of single point mutations, it has

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