Metabolism of alpha- and beta-adrenergic receptors in vitro and in vivo

Abstract

Despite considerable evidence that changes in number of adrenergic receptors can occur under various conditions, knowledge of the mechanisms mediating these changes is still rudimentary. As discussed, indirect approaches emphasizing the kinetics of receptor turnover have been the principal means of investigation. These indirect methods, which depend on the ability of a radioligand to detect the receptors, are limited by several factors. Even so, the data obtained using indirect approaches, in particular on various model systems in cell culture, lead to several conclusions: Both alpha 1- and beta-adrenergic receptors are metabolized rather slowly in vitro under basal conditions, in the absence of exposure to agonists. Typical half-lives are greater than 20 hr, a turnover that is slower than that of several other classes of neurotransmitter and hormone receptors (9, 10, 12, 16). Moreover, alpha 1-adrenergic receptors and beta-adrenergic receptors can have substantially different half-lives, even when expressed on the same cell. In view of the relatively slow rate of disappearance of adrenergic receptors under basal conditions, settings in which receptor number increases are almost certainly to result from increases in one or more of the factors that contribute to the rate of receptor appearance on the plasma membrane. Treatment of cells with agonists markedly shortens the half-life of alpha 1- and beta-adrenergic receptors. This shortened half-life results primarily from an enhanced loss of receptors from the plasma membrane, and not from agonist-induced attenuation of receptor appearance. In fact, data acquired from studies of receptor recovery after agonist-induced down-regulation suggest that rates of receptor reappearance are markedly enhanced through either receptor recycling or an increase in receptor synthesis. Limited studies conducted in vivo yield qualitatively similar results to those observed in in vitro studies of the metabolism of adrenergic receptors. In general, adrenergic receptors in the CNS turn over more slowly than those in peripheral tissues. These conclusions help to highlight the many aspects of metabolism of adrenergic receptors that are as yet unknown, including identification and characterization of the cellular machinery responsible for receptor metabolism, elucidation of the molecular events that control metabolism, and assessment of how drugs and other factors influence these events. Future studies are likely to be based on the development of new methodology with antireceptor antibodies, receptor cDNA's, and improved morphological methods (autoradiography, immunohistochemistry, etc).(ABSTRACT TRUNCATED AT 400 WORDS)