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Research ArticleArticle

Effects of Regulators of G Protein-Signaling Proteins on the Functional Response of the μ-Opioid Receptor in a Melanophore-Based Assay

Marc N. Potenza, Stephen J. Gold, Alison Roby-Shemkowitz, Michael R. Lerner and Eric J. Nestler
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 482-491;
Marc N. Potenza
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Stephen J. Gold
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Alison Roby-Shemkowitz
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Michael R. Lerner
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Eric J. Nestler
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Abstract

The goal of the present study was to investigate a possible role for regulators of G protein-signaling (RGS) proteins in opioid receptor (OR) desensitization using cultured Xenopus laevis dermal melanophores. Morphine-induced pigment aggregation in a melanophore cell line stably expressing the murine μ OR (μOR) was quantified over time. Responses of the μOR (a Gi-linked receptor) exhibited a time-dependent desensitization, which varied with the concentration of morphine used. In contrast, much less desensitization was observed in response to melatonin, effects mediated through the cells’ endogenous melatonin receptor (which is also Gi-linked). To further study OR desensitization, melanophores lacking a μOR were transiently transfected with plasmids encoding the μOR alone or in combination with plasmids encoding one of several RGS subtypes (RGS1, RGS2, RGS3, or RGS4). Overexpression of RGS2, but not the other RGS subtypes, produced a rightward shift in the morphine concentration-response curve. RGS protein overexpression also decreased the magnitude of morphine-induced responses. Finally, the effect of a mutant form of Gαi1, which is insensitive to RGS action, was investigated with respect to its ability to alter the response of the μOR to morphine. Expression of the mutant Gαi1prolonged morphine-induced pigment aggregation and produced leftward shifts in concentration-response curves, compared with expression of wild-type Gαi1. These results demonstrate that specific RGS proteins can dampen signals initiated by agonist activation of the μOR, and support a possible role for RGS proteins in OR desensitization.

Footnotes

  • Send reprint requests to: Eric J. Nestler, Connecticut Mental Health Center, 34 Park St., New Haven, CT 06508. E-mail:eric.nestler{at}yale.edu

  • ↵1 This research was supported by grants from the National Institute on Drug Abuse (to E.J.N.) and the National Institute of Mental Health (to E.J.N.), a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression (to M.N.P.), a Biological Sciences Training Program training grant (to M.N.P.), and by the Connecticut Mental Health Center. The research presented in this publication was recognized with a Lilly/APA Resident Research Award (to M.N.P.).

  • Abbreviations:
    OR
    opioid receptor
    RGS
    regulators of G protein signaling
    β2AR
    β2-adrenergic receptor
    D2R
    D2B dopamine receptor
    GRKs
    G protein-coupled receptor kinases
    μOR
    μ opioid receptor
    • Received January 28, 1999.
    • Accepted June 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Effects of Regulators of G Protein-Signaling Proteins on the Functional Response of the μ-Opioid Receptor in a Melanophore-Based Assay

Marc N. Potenza, Stephen J. Gold, Alison Roby-Shemkowitz, Michael R. Lerner and Eric J. Nestler
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 482-491;

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Research ArticleArticle

Effects of Regulators of G Protein-Signaling Proteins on the Functional Response of the μ-Opioid Receptor in a Melanophore-Based Assay

Marc N. Potenza, Stephen J. Gold, Alison Roby-Shemkowitz, Michael R. Lerner and Eric J. Nestler
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 482-491;
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