Evidence for transduction of mu but not kappa opioid modulation of extracellular signal-regulated kinase activity by G(z) and G(12) proteins

Chronic treatment with mu or kappa opioid agonists (greater than or equal t o 2. h) inhibits EGF-induced ERK activation in opioid receptor overexpressi ng COS-7 cells. Although acute mu and kappa opioids activate ERK via a pert ussis toxin-sensitive G protein, pertussis toxin insensitivity of the chron ic mu (but not kappa) action was observed. Here, we tested several pertussi s toxin-insensitive G proteins as candidates to transduce acute and/or chro nic opioid modulation of ERK. Overexpressed G alpha(z) (but not G alpha(12) ) transduced acute mu (but not kappa) ERK activation in pertussis toxin-tre ated COS-7 cells. Chronic mu (but not kappa) inhibited EGF stimulation of E RK in pertussis toxin-treated cells overexpressing G alpha(z), or G alpha(1 2). Transfection of G alpha(13) or G alpha(q) blocked inhibition under the same conditions. Overexpressed interfering and non-interfering G alpha(z) m utants differentially affected mu inhibition of ERK consistent with G(z) tr ansduction. In this and prior studies, G alpha(z) and G alpha(12) immunorea ctivity were detected in untransfected COS-7 cells, suggesting that these G proteins may be endogenous mediators of chronic mu inhibitory actions on E RK. (C) 2000 Elsevier Science Inc. All rights reserved.