Adrenergic receptors specificity

The adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors, which are the targets of catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines, epinephrine, and norepinephrine (also called adrenaline and noradrenaline), and are activated by these. 

Cyclic AMP is eventually eliminated by cAMP phosphodiesterase, and Gs turns itself off by hydrolysis of its bound GTP to GDP. When the epinephrine signal persists, j8-adrenergic receptor-specific protein kinase and arrestin 2 temporarily desensitize the receptor and cause it to move into intracellular vesicles. In some cases, arrestin also acts as a scaffold protein, bringing together protein components of a signaling pathway such as the MAPK cascade. 

Non-adrenergic receptors specific for imidazolinelike compounds do exist and are physically different from the classical a 2-adrenoceptors. 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Some of these protein kinases are specific for particular receptors (e.g., 3-adrenergic receptor kinase [pARK], now referred to as GRK2). 

Kable, J. W., Murrin, L. C. and Bylund, D. B. In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors. /. Pharmacol. Exp. Ther. 293 1-7, 2000. 

Because of their reflex cardiac effect, vasodilators, if used alone in the treatment of hypertension, have not been a successful therapeutic tool. However, the reflex tachycardia and increase in cardiac output can be effectively blocked by the therapeutic association with a sympathetic blocker guanethidine, reserpine, methyldopa, or clonidine. More specifically, blockade of the cardiac beta-adrenergic receptors will also prevent the cardiac response to hydralazine. Thus, the therapeutic combination of hydralazine and propranolol can be successfully employed for effective blood pressure reduction(11). 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

Lohse, M. J., Benovic, J. L., Caron, M. G., and Lefkowitz, R. J. (1990) Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors. J. Biol. Chem. 265, 3202-3211. 

Shih, M., and Malbon, C. C. (1994) Oligodeoxynucleotides antisense to mRNA encoding protein kinase A, protein kinase C, and beta-adrenergic receptor kinase reveal distinctive cell-type-specific roles in agonist-induced desensitization. Proc. Natl. Acad. Sci. U. S. A. 91, 12193-12197. 

These drugs are peripheral coronary vasodilating drugs with a-adrenoblocking activity that differ only in specificity to aj-adrenoreceptors. Unlike phenoxybenzamine and phentolamine (described above), they selectively block aj-receptors and have little affinity with Oj-adrenergic receptors. 

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