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Phosphorylation of G_s Influences Its Association with the µ-Opioid Receptor and Is Modulated by Long-Term Morphine Exposure

Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York

The recent biochemical demonstration of the association of the µ-opioid receptor (MOR) with G_s that increases after long-term morphine treatment (Mol Brain Res 135:217–224, 2005) provides a new imperative for studying MOR-G_s interactions and the mechanisms that modulate it. A persisting challenge is to elucidate those neurochemical parameters modulated by long-term morphine treatment that facilitate MOR-G_s association. This study demonstrates that 1) G_s exists as a phosphoprotein, 2) the stoichiometry of G_s phosphorylation decreases after long-term morphine treatment, and 3) in vitro dephosphorylation of G_s increases its association with MOR. Furthermore, our data suggest that increased association of G_s with protein phosphatase 2A is functionally linked to the long-term morphine treatment-induced reduction in G_s phosphorylation. These findings are observed in MOR-Chinese hamster ovary and F11 cells as well as spinal cord, indicating that they are not idiosyncratic to the particular cell line used or a "culture" phenomenon and generalize to complex neural tissue. Taken together, these results indicate that the phosphorylation state of G_s is a critical determinant of its interaction with MOR. Long-term morphine treatment decreases G_s phosphorylation, which is a key mechanism underlying the previously demonstrated increased association of MOR and G_s in opioid tolerant tissue.

Received for publication March 19, 2007.

Accepted for publication June 15, 2007.

Address correspondence to: Dr. Alan Gintzler, Box 8, Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. E-mail: alan.gintzler{at}downstate.edu

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