REGULATION OF ALPHA-2 ADRENERGIC RECEPTORS

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Norepinephrine and epinephrine are important neurotransmitters in the central nervous system, and alpha-2 adrenergic receptors, which are coupled to the inhibition of adenylate cyclase, are widely distributed. Clinicallly, alpha-2 adrenergic agonists such as clonidine and guanabenz are used to treat hypertension as well as several other disorders. While clonidine is thought to act centrally to control blood pressure, its mechanism of action is not well understood. The therapeutic effects of alpha-2 adrenergic agonists often are ivident only after chronic treatment, suggesting the involvement of adaptive changes. Thus, a better understanding of the regulation and the mechanism of action of alpha-2 adrenergic receptors, their coupling to and their regulation of adenylate cyclase, has a clear potential for the development of better drug therapies. The overall goal of the proposed research is to understand the molecular basis for the effects of incubation and preincubation of cells with an alpha-2 adrenergic agonist on subsequent alpha-2 adrenergic receptor binding and the activity of the enzyme adenylate cyclase. There are three effects to be studied. The first is the down-regulation of receptor number and desensitization of the cyclic AMP response. The second is the sensitization of stimulated cyclic AMP production following preincubation with an alpha-2 agonist. There appear to be two types of sensitization, which may have different mechanisms. The third effect is the potentiation of forskolin-stimulated cyclic AMP production by concurrent incubation with (a high concentration of) an alpha-2 agonist. We propose to determine the mechanisms of these effects in three cell lines, each of which express one of the three putative alpha-2 adrenergic receptor subtypes, and then determine if any differences are cell type specific or receptor subtype specific (or perhaps a combination of both). Our overall approach is to first study the mechanism of these phenomena in the three cell lines which normally express each alpha-2 adrenergic receptor subtype, and then to study a cell line (which normally lacks the receptor) stably transfected separately with each of the subtypes.