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.
Tso
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PH
Department of Biochemistry and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Wong
Y H
YH
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology*; D037342:Pertussis Toxin; D010766:Phosphorylation; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D017362:Cyclic AMP Response Element-Binding Protein; C099387:GNAZ protein, human; D044385:GTP-Binding Protein alpha Subunits; C490963:Gnaz protein, rat; D009294:Narcotics; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D037342:Pertussis Toxin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases