Translocation and Uncoupling of theβ-Adrenergic Receptor in Rat Lung after Catecholamine Promoted Desensitizationin Vivo

Abstract

.beta.-Adrenergic agonists and antagonists are widely used in many clinical situations to regulate .beta.-adrenergic stimulation. Responsiveness to .beta.-stimulation may be reduced by the process of desensitization. An in vivo mammalian model system, the rat lung, was established to study the cellular and biochemical basis for .beta.-agonist induced desensitization. After in vivo administration of a .beta.-agonist [(-)isoproterenol] the adenylate cyclase becomes rapidly insensitive to further stimulation by .beta.-agonists with no change in basal or NaF-stimulated activity. The in vivo desensitization can be blocked by the simultaneous administration of a .beta.-antagonist [(.+-.)propranolol] and the process displays the pharmacological characteristics typifying the .beta.2 receptor of rat lung. This indicates that the in vivo desensitization is itself a receptor-mediated event. The processes of de- and resensitization are very rapid with onset within 5 min, maximal effect at 10 min, and complete reversal by 2-3 h. The change of adenylate cyclase sensitivity is paralleled by a translocation of .apprx. 40% of the .beta.-receptors from the plasma membrane fraction to a light membrane fraction, which has very low activities of plasma membrane marker enzymes. The receptors translocated to the light membrane fraction as well as those remaining in the plasma membranes are uncoupled with loss of their ability to form the high affinity, nucleotide sensitive, physiologically active state of the receptor. During resensitization the receptors in the plasma membrane fraction are recoupled before all the translocated receptors have returned. Translocation and uncoupling of the receptors are apparently 2 distinct, probably independent processes. During the entire process of de- and resensitization no structural change of the receptor protein residing in the plasma membranes or light membrane fraction can be demonstrated as visualized by photoaffinity labeling.