Adrenergic Receptors

The «and ^catecholamine receptors were first discovered more than 50 years ago (Alhquist 1948) and later subdivided further into ,rci, and "2#■ and l 3 adrenoreceptors—all of which are GPCRs—on the basis of molecular cloning and pharmacological and biochemical studies (see Figure 1-5B).

There are three subtypes of c 1 receptors, denoted 1A, IB, and ID; they are all positively coupled to PLC and possibly phospholipase A2 (see Figure 1-5B). The °*2 family comprises the 2A/D, 2B, and 2C subtypes, which couple negatively to adenylyl cyclase and regulate K+ and Ca2+ channels (see Figure 1-5B). The 2A, 2B, and 2C adrenoceptors correspond to the human genes ■2-CIO^i-d, and «2~C4, respectively (see Bylund et al. 1994). The bovine, guinea pig, rat, and mouse a2D adrenoreceptor is thought to be a species homolog or variant of the human «2A adrenoreceptor (Bylund et al. 1994) and is often referred to as '-J2A/D- The "2 receptors represent autoreceptors for NE neurons, and blockade of these autoreceptors results in increased NE release—a biochemical effect that has been postulated to play a role in the mechanisms of action of selected antidepressants (e.g., mianserin, mirtazapine) and antipsychotics (e.g., clozapine). In the LC, 2-adrenergic receptors converge onto similar K+ channels as1 opioid receptors, and this convergence has been postulated to represent a mechanism for the efficacy of clonidine (an "2 agonist) in attenuating some of the physical symptoms of opioid withdrawal. Thec'2 antagonist yohimbine, which robustly increases NE neuron firing and NE release, has been used as a provocative challenge in clinical studies of anxiety disorders and as an antidepressant-potentiating agent. Given that NE neurons colocalize and release orexins, it is of interest that this neuropeptide has been implicated in sleep disorders and hypoglycemia through its glucose-sensing tandem-pore K+ (K2P) effects in coordinating arousal (M. M. Scott et al. 2006).


The 1 receptor family comprises 'i, 1 2, and 3 adrenoreceptors, which are all positively coupled to adenylyl cyclase (Bylund et al. 1994) (see Figure 1-5B). As is discussed in greater detail in the chapters on antidepressants and anxiolytics (see Chapters 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26), most effective antidepressants produce a downregulation/desensitization of L 1 receptors in rat forebrain, leading to the suggestion that these effects may play a role in their therapeutic efficacy. Interestingly, 1 receptors have also been shown to play a role in regulating emotional memories, leading to the proposal that 1 antagonists may have utility in the treatment of posttraumatic stress disorder (PTSD) (Cahill et al. 1994; Przybyslawski et al. 1999). ^3 receptors are not believed to be present in the CNS but are abundantly expressed on brown fat, where they exert lipolytic and thermogenic effects. Not surprisingly, there is active research attempting to develop selective $3 agonists for the treatment of obesity.

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