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J Biol Chem, Vol. 275, Issue 17, 12900-12908, April 28, 2000

Selective Regulation of Endogenous G Protein-coupled Receptors by Arrestins in HEK293 Cells^*

Stuart J. Mundell and Jeffrey L. Benovic

From the Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Arrestins play an important role in regulating desensitization and trafficking of G protein-coupled receptors (GPCRs). However, limited insight into the specificity of arrestin-mediated regulation of GPCRs is currently available. Recently, we used an antisense strategy to reduce arrestin levels in HEK293 cells and characterize the role of arrestins on endogenous G_s-coupled receptors (Mundell, S. J., Loudon, R. B., and Benovic, J. L. (1999) Biochemistry 38, 8723-8732). Here, we characterized GPCRs coupled to either G_q (M₁ muscarinic acetylcholine receptor (M₁AchR) and P2y₁ and P2y₂ purinergic receptors) or G_i (somatostatin and AT1 angiotensin receptors) in wild type and arrestin antisense HEK293 cells. The agonist-specific desensitization of the M₁Ach and somatostatin receptors was significantly attenuated in antisense-expressing cells, whereas desensitization of P2y₁ and P2y₂ purinergic and AT1 angiotensin receptors was unaffected by reduced arrestin levels. To further examine arrestin/GPCR specificity, we studied the effects of endogenous GPCR activation on the redistribution of arrestin-2 epitope tagged with the green fluorescent protein (arrestin-2-GFP). These studies revealed a receptor-specific movement of arrestin-2-GFP that mirrored the arrestin-receptor specificity observed in the antisense cells. Thus, agonist-induced activation of endogenous ₂-adrenergic, prostaglandin E₂, M₁Ach, and somatostatin receptors induced arrestin-2-GFP redistribution to early endosomes, whereas P2y₁ and P2y₂ purinergic and AT1 angiotensin receptor activation did not. Thus, endogenous arrestins mediate the regulation of selective G_q- and G_i-coupled receptors in HEK293 cells.

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^* This work was supported by National Institutes of Health Grant GM47417.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.

To whom correspondence should be addressed: Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107. Tel.: 215-503-607; Fax: 215-923-1098; E-mail: benovic@lac.jci.tju.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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