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Vol. 291, Issue 2, 482-491, November 1999
Laboratory of Molecular Psychiatry (M.N.P., S.J.G., A.R.-S.,
E.J.N.); Departments of Psychiatry, 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
G
i1, 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 Gi1
prolonged morphine-induced pigment aggregation and produced leftward
shifts in concentration-response curves, compared with expression of
wild-type Gi1. 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.
0022-3565/99/2912-0482$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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