Evidence for transduction of mu but not kappa opioid modulation of extracellular signal-regulated kinase activity by Gz and G12 proteins

Chronic treatment with mu or kappa opioid agonists (greater than or equal to 2. h) inhibits EGF-induced ERK activation in opioid receptor overexpressing COS-7 cells. Although acute mu and kappa opioids activate ERK via a pertussis toxin-sensitive G protein, pertussis toxin insensitivity of the chronic mu (but not kappa) action was observed. Here, we tested several pertussis toxin-insensitive G proteins as candidates to transduce acute and/or chronic opioid modulation of ERK. Overexpressed G alpha(z) (but not G alpha(12)) transduced acute mu (but not kappa) ERK activation in pertussis toxin-treated COS-7 cells. Chronic mu (but not kappa) inhibited EGF stimulation of ERK in pertussis toxin-treated cells overexpressing G alpha(z), or G alpha(12). Transfection of G alpha(13) or G alpha(q) blocked inhibition under the same conditions. Overexpressed interfering and non-interfering G alpha(z) mutants differentially affected mu inhibition of ERK consistent with G(z) transduction. In this and prior studies, G alpha(z) and G alpha(12) immunoreactivity were detected in untransfected COS-7 cells, suggesting that these G proteins may be endogenous mediators of chronic mu inhibitory actions on ERK. (C) 2000 Elsevier Science Inc. All rights reserved.