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J. Biol. Chem., Vol. 277, Issue 11, 9570-9579, March 15, 2002
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From the Departments of Despite important roles in myocardial hypertrophy
and benign prostatic hyperplasia, little is known about acute effects
of agonist stimulation on
Acute Agonist-mediated Desensitization of the Human
1a-Adrenergic Receptor Is Primarily Independent of
Carboxyl Terminus Regulation
IMPLICATIONS FOR REGULATION OF 
1aAR SPLICE
VARIANTS*
§,
,¶**
Pharmacology and Cancer
Biology, ¶ Anesthesiology, and ** Surgery, Duke
University Medical Center, Durham, North Carolina 27710
1a-adrenergic receptor
(1aAR) signaling and function. Regulatory mechanisms are
likely complex since 12 distinct human 1aAR
carboxyl-terminal splice variants have been isolated. After determining
the predominance of the 1a-1AR isoform in
human heart and prostate, we stably expressed an epitope-tagged 1a-1AR cDNA in rat-1 fibroblasts and subsequently
examined regulation of signaling, phosphorylation, and internalization
of the receptor. Human 1aAR-mediated inositol phosphate
signaling is acutely desensitized in response to both agonist and
phorbol 12-myristate 13-acetate (PMA) exposure. Concurrent with
desensitization, 1aARs in
32Pi-labeled cells are rapidly phosphorylated
in response to both NE and PMA stimulation. Despite the ability of PKC
to desensitize 1aARs 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 1aARs. Internalization of cell
surface 1aARs also occurs in response to agonist
stimulation (but not PKC activation), but is initiated more slowly than
receptor desensitization. Significantly, deletion of the
1aAR 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 1aARs are primarily independent of
the carboxyl terminus, they may be common to all functional
1aAR isoforms.
*
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.
Present address: School of Veterinary Medicine, University of
Pennsylvania, Philadelphia, PA 19104.
Senior fellow in the Center for the Study of Aging and Human
Development, Duke University Medical Center. To whom correspondence should be addressed: Professor of Anesthesiology, Pharmacology/Cancer Biology, and Surgery, Box 3094, Dept. of Anesthesiology, Duke University Medical Center, Durham, NC 27710. Tel.: 919-681-4781; Fax:
919-681-4776; E-mail: schwi001@mc.duke.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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