INFLUENCE OF CELL-TYPE UPON THE DESENSITIZATION OF THE BETA(3)- ADRENERGIC-RECEPTOR

Previous studies have suggested that the beta(3) receptor fails to bec ome desensitized following acute agonist exposure. We have determined whether this resistance to desensitization is an intrinsic property of the human beta(3) receptor by examining beta(3) receptor-stimulated a denylyl cyclase activity in several cell types. Prior exposure to ISO significantly decreased beta(3) receptor-stimulated adenylyl cyclase a ctivity in SK-N-MC human neuroepithelioma cells, which natively expres s the beta(3) receptor. ISO pretreatment significantly desensitized th e recombinant beta(3) receptor when stably expressed in 293 cells, but not when the receptor was expressed in Chinese hamster ovary cells. M utant receptors lacking the second exon of the human beta(3) receptor also underwent agonist-induced desensitization when expressed in 293 c ells. Additionally, the rat beta(3), receptor, which fails to desensit ize in rat adipocytes, underwent agonist-induced desensitization when expressed in 293 cells. Pretreatment with CGP 12177A, a beta(3)-select ive agonist, also reduced beta(3)-stimulated adenylyl cyclase activity in transfected 293 cells. In contrast, 8-Br-Cyc AMP did not desensiti ze the beta(3) receptor. Concanavalin A, an inhibitor of receptor sequ estration failed to prevent ISO-induced desensitization of the beta(3) receptor. Furthermore, radioligand binding studies showed that ISO pr etreatment did not cause a loss of beta(3) receptors from 293 cell mem branes. The results of the present study indicate that beta(3) recepto r desensitization is dependent upon the cellular background in which t his receptor is expressed. Furthermore, the mechanism responsible for beta(3) receptor desensitization does not appear to involve sequestrat ion, cyclic AMP-dependent phosphorylation or down-regulation of the re ceptor.