Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.

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Abstract
Homologous (agonist-specific) desensitization of .beta.-adrenergic receptors (.beta.ARs) is accompanied by and appears to require phosphorylation of the receptors. We have recently described a novel protein kinase, .beta.AR kinase, which phosphorylates .beta.ARs in vitro in an agonist-dependent manner. This kinase is inhibited by two classes of compounds, polyanions and synthetic peptides derived from the .beta.2-adrenergic receptor (.beta.2AR). In this report we describe the effects of these inhibitors on the process of homologous desensitization induced by the .beta.-adrenergic agonist isoproterenol. Permeabilization of human epidermoid carcinoma A431 cells with digitonin was used to permit access of the charged inhibitors to the cytosol; this procedure did not interfere with the pattern of isoproterenol-induced homologous desensitization of .beta.2AR-stimulated adenylyl cyclase. Inhibitors of .beta.AR kinase markedly inhibited homologous desensitization of .beta.2ARs in the permeabilized cells. Inhibition of desensitization by heparin, the most potent of the polyanion inhibitors of .beta.AR kinase, occurred over the same concentration range (5-50 nM) as inhibition of purified .beta.AR kinase assessed in a reconstituted system. Inhibition of desensitization by heparin was accompanied by a marked reduction of receptor phosphorylation in the permeabilized cells. Whereas inhibitors of .beta.AR kinase inhibited homologous desensitization, inhibitors of protein kinase C and of cyclic-nucleotide-dependent protein kinases were ineffective. These data establish that phosphorylation of .beta.ARs by .beta.AR kinase is an essential step in homologous desensitization of the receptors. They further suggest a potential therapeutic value of inhibitors of .beta.AR kinase in inhibiting agonist-induced desensitization.

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