G

Gq G

?

Examples of Some Biochemical Effectors

T adenylyl cyclase, T L-type Ca2+ channels T adenylyl cyclase T adenylyl cyclase T phospholipase C T phospholipase D T phospholipase A2 ? T Ca2+ channels ■!• adenylyl cyclase T K+ channels

■!• Ca2+ channels (L- and N-type) T PLC,PLA, subtypes (¡¡i ¡32 and b3) couple to Gs and activate adenylyl cyclase (Table 6-6). Thus, stimulation of ¡3 adrenergic receptors leads to the accumulation of cyclic AMP, activation of PKA, and altered function of numerous cellular proteins as a result of their phosphorylation (see Chapter 1). In addition, Gs can enhance directly the activation of voltage-sensitive Ca2+ channels in the plasma membrane of skeletal and cardiac muscle. Catecholamines promote ¡3 receptor feedback regulation, i.e., desensitization and receptor down-regulation, and ¡3 receptors differ in the extent to which they undergo such regulation, with the ¡32 receptor being the most susceptible. ¡3p ¡3? and b3 receptors may differ in their signaling pathways and subcellular location in experimental systems, and coupling to Gi is possible, probably due to subtype-selective association with intra-cellular scaffolding and signaling proteins. The activation of PKA by cyclic AMP and the importance of compartmentation of components of the cyclic AMP pathway are discussed in Chapter 1.

a ADRENERGIC RECEPTORS

The ai receptors (a1A, a^, and aw) and a2 receptors (a2A, a2B, and a2c) are GPCRs. a2 receptors couple to a variety of effectors (Table 6-6), generally inhibiting adenylyl cyclase and activating G protein—gated K+ channels, resulting in membrane hyperpolarization (possibly via Ca2+-dependent processes or from direct interaction of liberated ¡3g subunits with K+ channels). a2 receptors also can inhibit voltage-gated Ca2+ channels, an effect mediated by G . Other second-messenger systems linked to a2-receptor activation include acceleration of Na+/H+ exchange, stimulation of phospholipase C^ activity and arachidonic acid mobilization, increased phosphoinositide hydrolysis, and increased intracellular availability of Ca2+. The latter is involved in the smooth muscle—contracting effect of a2 adrenergic receptor agonists. The a2A receptor plays a major role in inhibiting NE release from sympathetic nerve endings and suppressing sympathetic outflow from the brain, leading to hypotension. In the CNS, a2A receptors, the most dominant adrenergic receptor, probably produce the antinociceptive effects, sedation, hypothermia, hypotension, and behavioral actions of a2 agonists. The a2B receptor is the main receptor mediating a2-induced vasoconstriction, whereas the a2C receptor is the predominant receptor inhibiting the release of catecholamines from the adrenal medulla and modulating DA neurotransmission in the brain.

Stimulation of ai receptors results in the regulation of multiple effector systems, primarily activation of the G-PLC¡-IP-Ca2+ pathway and the activation of other Ca2+- and calmodulin-sensitive pathways and the activation of PKC. PKC phosphorylates many substrates, including membrane proteins such as channels, pumps, and ion-exchange proteins (e.g., Ca2+-transport ATPase). These effects presumably lead to regulation of various ion conductances a ^receptor stimulation of phospholipase A2 leads to the release of free arachidonate, which is then metabolized via the cyclooxygenase and lipoxygenase pathways to the bioactive prostaglandins and leukotrienes, respectively (see Chapter 25). Stimulation of phospholipase A2 activity by various agonists (including Epi acting at at receptors) is found in many tissues, suggesting that this effector is physiologically important. Phospholipase D hydrolyzes phosphatidylcholine to yield phos-phatidic acid (PA). Although PA itself may act as a second messenger by releasing Ca2+ from intracellular stores, it also is metabolized to the second messenger DAG. Phospholipase D is an effector for ADP-ribosylating factor (ARF), suggesting that phospholipase D may play a role in membrane trafficking. Finally, some evidence in vascular smooth muscle suggests that at receptors are capable of regulating a Ca2+ channel via a G protein.

In most smooth muscles, the increased concentration of intracellular Ca2+ ultimately causes contraction as a result of activation of Ca2+-sensitive protein kinases such as the calmodulin-dependent myosin light-chain kinase; phosphorylation of the light chain of myosin is associated with the development of tension. In contrast, the increased concentration of intracellular Ca2+ that results from stimulation of ai receptors in GI smooth muscle causes hyperpolarization and relaxation by activation of Ca2+-dependent K+ channels. The a1A receptor is the predominant receptor causing vasoconstriction in many vascular beds, including the mammary, mesenteric, splenic, hepatic, omental, renal, pulmonary, and epicardial coronary arteries. It is also the predominant subtype in the vena cava and the saphenous and pulmonary veins. Together with the a^ receptor subtype, its activation promotes cardiac growth. The a^ receptor subtype is the most abundant subtype in the heart, whereas the a id receptor subtype is the predominant receptor causing vasoconstriction in the aorta. Some evidence suggests that a^ receptors mediate behaviors such as reaction to novelty and exploration and are involved in behavioral sensitizations and in the vulnerability to addiction (see Chapter 23).

Localization of Adrenergic Receptors—Presynaptically located a2 and ¡32 receptors fulfill important roles in the regulation of neurotransmitter release from sympathetic nerve endings (see above). Presynaptic a2 receptors also may mediate inhibition of release of neurotransmitters other than NE in the central and peripheral nervous systems. Both a2 and ¡ 2 receptors are located on many types of neurons in the brain. In peripheral tissues, postsynaptic a2 receptors are found in vascular and other smooth muscle cells (where they mediate contraction), adipocytes, and many types of secretory epithelial cells (intestinal, renal, endocrine). Postsynaptic ¡¡2 receptors are found in the myocardium (where they mediate contraction) as well as on vascular and other smooth muscle cells (where they mediate relaxation). Both a2 and ¡2 receptors may be situated at sites that are relatively remote from nerve terminals releasing NE. Such extrajunctional receptors typically are found on vascular smooth muscle cells and blood elements (platelets and leukocytes) and may be activated preferentially by circulating catecholamines, particularly Epi. In contrast, a, and receptors appear to be located mainly in the immediate vicinity of sympathetic adrenergic nerve terminals in peripheral target organs, strategically placed to be activated during stimulation of these nerves. These receptors also are distributed widely in the mammalian brain.

The cellular distributions of the three a, and three a2 receptor subtypes still are incompletely understood. Recent findings indicate that a2A subtype functions as a presynaptic autoreceptor in central noradrenergic neurons.

REFRACTORINESS TO CATECHOLAMINES Exposure of catecholamine-sensitive cells and tissues to adrenergic agonists causes a progressive diminution in their capacity to respond to such agents. This phenomenon, variously termed refractoriness, desensitization, downregula-tion, or tachyphylaxis, can limit the therapeutic efficacy and duration of action of catecholamines and other agents (see Chapter 1).

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