MECHANISMS OF SIGNAL TRANSDUCTION
Acute Agonist-mediated Desensitization of the Human α1a-Adrenergic Receptor Is Primarily Independent of Carboxyl Terminus Regulation: IMPLICATIONS FOR REGULATION OF α1aAR SPLICE VARIANTS*

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Despite important roles in myocardial hypertrophy and benign prostatic hyperplasia, little is known about acute effects of agonist stimulation on α1a-adrenergic receptor (α1aAR) signaling and function. Regulatory mechanisms are likely complex since 12 distinct human α1aAR carboxyl-terminal splice variants have been isolated. After determining the predominance of the α1a-1AR isoform in human heart and prostate, we stably expressed an epitope-tagged α1a-1AR cDNA in rat-1 fibroblasts and subsequently examined regulation of signaling, phosphorylation, and internalization of the receptor. Human α1aAR-mediated inositol phosphate signaling is acutely desensitized in response to both agonist and phorbol 12-myristate 13-acetate (PMA) exposure. Concurrent with desensitization, α1aARs in32Pi-labeled cells are rapidly phosphorylated in response to both NE and PMA stimulation. Despite the ability of PKC to desensitize α1aARs when directly activated with PMA, inhibitors of PKC have no effect on agonist-mediated desensitization. In contrast, involvement of GRK kinases is suggested by the ability of GRK2 to desensitize α1aARs. Internalization of cell surface α1aARs also occurs in response to agonist stimulation (but not PKC activation), but is initiated more slowly than receptor desensitization. Significantly, deletion of the α1aAR carboxyl terminus has no effect on receptor internalization or either agonist-induced or GRK-mediated receptor desensitization. Because mechanisms underlying acute agonist-mediated regulation of human α1aARs are primarily independent of the carboxyl terminus, they may be common to all functional α1aAR isoforms.

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Published, JBC Papers in Press, January 7, 2002, DOI 10.1074/jbc.M111762200

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This work was supported in part by National Institutes of Health Grants AG00745 and HL49103 (to D. A. S.). Human tissues were obtained via the Duke Rapid Autopsy Program (supported by National Institutes of Health Grant AG05128 and GlaxoWellcome, Inc.) and the Duke General Clinical Research Center (NIH-M01 RR30).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Present address: GlaxoSmithKline, Inc., RTP, NC 27709.

Present address: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.