Vol. 295, Issue 1, 168-176, October 2000

G_z Can Mediate the Acute Actions of µ- and -Opioids but Is Not Involved in Opioid-Induced Adenylyl Cyclase Supersensitization¹

Prudence H. Tso and Yung H. Wong

Department of Biochemistry and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

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