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MA Proll, RB Clark and RW Butcher
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston 77225-0334.
In the present study wild-type and various mutant hamster beta 2- adrenergic receptors (beta ARs) expressed in L cells were used to examine potential molecular mechanisms involved in the desensitization of hormonal stimulation of adenylyl cyclase observed after long term exposure to low concentrations of epinephrine. The mutant beta ARs included deletion mutants, D(259-262)beta AR and D(343-348)beta AR, that lack the consensus sites for cAMP-dependent protein kinase (cAPK) and protein kinase C (PKC) and a truncation mutant, T(354)beta AR, that lacks the putative consensus sites for beta AR kinase. Epinephrine stimulation of adenylyl cyclase was desensitized in all four cell lines after growth for 24 hr in the presence of 3 nM epinephrine, and this desensitization was characterized by a 3-4-fold increase in the EC50 for epinephrine stimulation of adenylyl cyclase. In addition, the Vmax was significantly decreased in the cells with the wild-type beta AR and the D(343-348)beta AR. The desensitization was not masked by high concentrations of magnesium and was accompanied by a 40-70% down- regulation of beta ARs. In the cells treated with 3 nM epinephrine, prostaglandin E1 stimulation of adenylyl cyclase was decreased 11% in cells with the wild-type beta AR and forskolin stimulation was decreased 25-36% with all but the D(259-262)beta AR mutant. These results demonstrated that phosphorylations of the cAPK/PKC consensus sites and the serine- and threonine-rich segment of the carboxyl- terminal tail of the beta AR were not required for the desensitization caused by 3 nM epinephrine, thus further differentiating it from cAPK- or PKC-mediated desensitization and the desensitization attributed to beta AR kinase.
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