Gz can mediate the acute actions of mu- and kappa-opioids but is not involved in opioid-induced adenylyl cyclase supersensitization

The three subtypes of opioid receptors ( delta, mu, and kappa) are known to regulate multiple effectors through either pertussis toxin-sensitive or -i nsensitive G proteins. In opioid-induced inhibition of adenylyl cyclase, bo th G(i) and G(z) proteins can serve as the signal transducer. Our previous study showed that opioid-induced adenylyl cyclase supersensitization in hum an embryonic kidney (HEK) 293 cells expressing the delta-opioid receptor re quires G(i) but not G(z) proteins. Herein, we studied the ability of mu-and and kappa-opioid receptors to regulate the activities of adenylyl cyclase through G(z). In HEK 293 cells coexpressing G(z) with the mu- or kappa-opio id receptors, opioid agonists induced inhibition of adenylyl cyclase in a p ertussis toxin-insensitive manner. However, adenylyl cyclase supersensitiza tion induced by chronic opioid treatments remained sensitive to pertussis t oxin. We also showed that the responsiveness of cAMP-dependent response ele ment-binding proteins to forskolin was not altered after prolonged opioid t reatment but was higher in cells coexpressing G(z). Although the mu- and ka ppa-opioid receptors mediated acute activation of extracellular signal-regu lated protein kinase 1/2 via both G(i) and G(z), these responses were aboli shed by chronic opioid treatment. These studies showed that G(z) could medi ate acute actions of mu- and kappa-opioids but G(z) alone was insufficient to mediate adenylyl cyclase supersensitization induced by the chronic activ ation of opioid receptors.