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| Effects of regulators of G protein-signaling proteins on the functional response of the mu-opioid receptor in a melanophore-based assay |
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| Author(s): Potenza MN, Gold SJ, Roby-Shemkowitz A, Lerner MR, Nestler EJ |
| Source: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Volume: 291 Issue: 2 Pages: 482-491 Published: NOV 1999 |
| Times Cited: 40 References: 33 |
| 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 mu OR (mu OR) was quantified over time. Responses of the mu OR (a G(i)-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 G(i)-linked). To further study OR desensitization, melanophores lacking a mu OR were transiently transfected with plasmids encoding the mu OR alone or in combination with plasmids encoding one of several RGS sub-types (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 G(alpha i1), which is insensitive to RGS action, was investigated with respect to its ability to alter the response of the mu OR to morphine. Expression of the mutant G(alpha i1) prolonged morphine-induced pigment aggregation and produced leftward shifts in concentration-response curves, compared with expression of wild-type G(alpha i1). These results demonstrate that specific RGS proteins can dampen signals initiated by agonist activation of the mu OR, and support a possible role for RGS proteins in OR desensitization. |
| Document Type: Article |
| Language: English |
| Reprint Address: Nestler, EJ (reprint author), Yale Univ, Sch Med, Lab Mol Psychiat, New Haven, CT 06520 USA |
Addresses:
1. Yale Univ, Sch Med, Lab Mol Psychiat, New Haven, CT 06520 USA
2. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA
3. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT USA
4. Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA
5. Connecticut Mental Hlth Ctr, New Haven, CT USA
6. Univ Texas, SW Med Ctr, Dept Dermatol, Dallas, TX USA |
| Publisher: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA |
| Subject Category: Pharmacology & Pharmacy |
| IDS Number: 246DW |
| ISSN: 0022-3565 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |