Characterization of alpha 1- and alpha 2-adrenergic receptors

Within the short period of 5 years, the availability of a variety of specific radioligands has allowed the resolution of alpha 1- and alpha 2-adrenergic receptor populations in many different tissues and enabled researchers to begin investigations of the mechanisms of regulation and coupling of alpha 1 and alpha 2 receptors to their different cellular effector systems. Binding data have demonstrated that the pharmacological properties of each type of alpha receptor are, in general, similar across tissues and species, although there are some differences in the relative affinities of antagonist drugs. Further attempts to subclassify alpha 1 and alpha 2 receptors may be expected in the future. The historical development of the interpretation of [3H]clonidine binding is of interest in this regard. [3H]Clonidine was proposed to label the "agonist state" of the alpha receptor, and then to label alpha 2 receptors. It is now thought that it labels the agonist state of alpha 2 receptors. Might it actually label a subpopulation of alpha 2 receptors or just the agonist state of that subpopulation? Alpha-1 receptors by and large appear to occur in a single-affinity state with respect to both agonists and antagonists. By comparison, alpha 2 receptors may exist in multiple-affinity states reflecting the ability of the alpha 2 binding site protein to complex to additional membrane proteins which themselves are receptors for the physiological substrates GTP, Na+, Mg2+, and possibly Ca2+-calmodulin. Binding studies have also strongly indicated that alpha 2 receptors in most, if not all, tissues are probably coupled in an inhibitory manner to adenylate cyclase, as has been demonstrated in platelets, adipocytes, and NG 108-15 cells. Clearly the present status of alpha-receptor research has left many questions unresolved. We still have no idea what membrane effector system and associated second messenger is coupled to the alpha 1 receptor. The prevailing belief is that Ca2+ and the membrane Ca2+ channel fulfill these roles. However, others have suggested that phosphoinositide turnover represents the proximal receptor response, and indeed a membrane-bound phospholipase C may play an analogous role to adenylate cyclase for other adrenergic receptors (Putney et al., 1980). There is, however, some evidence that in some situations alpha 1 receptors may directly stimulate adenylate cyclase, and guanine nucleotide modulation of agonist affinities at alpha 1-receptor sites has been reported. The significance of these data and reported modulatory effects of Na+ at alpha 1 receptors (Glossmann and Presek, 1979; Glossmann et al., 1981) is still to be resolved.(ABSTRACT TRUNCATED AT 400 WORDS)