Abstract

The three subtypes of opioid receptors (δ, μ, and κ) 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 δ-opioid receptor requires G_i but not G_z proteins. Herein, we studied the ability of μ- and κ-opioid receptors to regulate the activities of adenylyl cyclase through G_z. In HEK 293 cells coexpressing G_zwith the μ- or κ-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 μ- and κ-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_zcould mediate acute actions of μ- and κ-opioids but G_zalone was insufficient to mediate adenylyl cyclase supersensitization induced by the chronic activation of opioid receptors.