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Short- and Long-Term Regulation of Adenylyl Cyclase Activity by -Opioid Receptor Are Mediated by G_i2 in Neuroblastoma N₂A Cells

Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota

Activation of the opioid receptor results in short-term inhibition of intracellular cAMP levels followed by receptor desensitization and subsequent increase of cAMP above the control level (adenylyl cyclase superactivation). Using adenovirus to deliver pertussis toxin-insensitive mutants of the -subunits of G_i/o that are expressed in neuroblastoma Neuro2A cells (G_i2, G_i3, and G_o), we examined the identities of the G proteins involved in the short- and long-term action of the -opioid receptor (DOR). Pertussis toxin pretreatment completely abolished the ability of [D-Pen², D-Pen⁵]-enkephalin (DPDPE) to inhibit forskolin-stimulated intracellular cAMP production. Expression of the C352L mutant of G_i2, and not the C351L mutants of G_i3 or G_o, rescued the short-term effect of DPDPE after pertussis toxin treatment. The ability of G_i2 in mediating DOR inhibition of adenylyl cyclase activity was also reflected in the ability of G_i2, not G_i3 or G_o, to coimmunoprecipitate with DOR. Coincidently, after long-term DPDPE treatment, pertussis toxin treatment eliminated the antagonist naloxone-induced superactivation of adenylyl cyclase activity. Again, only the C352L mutant of G_i2 restored the adenylyl cyclase superactivation after pertussis toxin treatment. More importantly, the C352L mutant of G_i2 remained associated with DOR after long-term agonist and pertussis toxin treatment whereas the wild-type G_i2 did not. These data suggest that G_i2 serves as the signaling molecule in both DOR-mediated short- and long-term regulation of adenylyl cyclase activity.

Address correspondence to: Lei Zhang, Department of Pharmacology, Medical School, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455. E-mail: zhang247{at}umn.edu

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