G(z) 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, micro, and kappa) are known to regulate multiple effectors through either pertussis toxin-sensitive or -insensitive G proteins. In opioid-induced inhibition of adenylyl cyclase, both G(i) and G(z) proteins can serve as the signal transducer. Our previous study showed that opioid-induced adenylyl cyclase supersensitization in human embryonic kidney (HEK) 293 cells expressing the delta-opioid receptor requires G(i) but not G(z) proteins. Herein, we studied the ability of mu- 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-opioid receptors, opioid agonists induced inhibition of adenylyl cyclase in a pertussis toxin-insensitive manner. However, adenylyl cyclase supersensitization induced by chronic opioid treatments remained sensitive to pertussis toxin. We also showed that the responsiveness of cAMP-dependent response element-binding proteins to forskolin was not altered after prolonged opioid treatment but was higher in cells coexpressing G(z). Although the mu- and kappa-opioid receptors mediated acute activation of extracellular signal-regulated protein kinase 1/2 via both G(i) and G(z), these responses were abolished by chronic opioid treatment. These studies showed that G(z) could mediate acute actions of mu- and kappa-opioids but G(z) alone was insufficient to mediate adenylyl cyclase supersensitization induced by the chronic activation of opioid receptors.