Supersensitization of the adenylyl cyclase system in Chinese hamster ovary cells co-expressing cloned opioid receptors and Gz, a PTX-insensitive G protein.
Chronic and/or sustained stimulation of opioid receptors has been shown to lead to an increase in activity of the adenylyl cyclase (AC) system via pertussis toxin (PTX)-sensitive Gi/o, family G protein. In the present study, we examined whether supersensitization of the AC system is induced via a PTX-insensitive G protein, Gz, activation of which leads to the inhibition of AC activity. In Chinese hamster ovary (CHO) cells expressing either mu- or kappa-opioid receptors, acute treatment with morphine or U69,593, but not naloxone or norbinaltorphimine, respectively, suppressed forskolin-induced cyclic AMP (cAMP) accumulation, while sustained (4 h) treatment with the opioid agonists induced cAMP overshoot above the naive level (supersensitization of the AC system). Both effects were completely blocked by pretreatment with PTX. In CHO cells co-expressing mu- or kappa-opioid receptors and alpha(z), inhibitory effects of cAMP accumulation by acute treatment with the opioid agonists and supersensitization of the AC system by sustained treatment with them were induced despite pretreatment with PTX. These data suggest that supersensitization of the AC system is induced by sustained opioid agonist treatment not only via Gi/o but also via Gz.
Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
T
T
Ozawa
T
T
Nakagawa
M
M
Minami
M
M
Satoh
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D044482:Benzeneacetamides; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D044385:GTP-Binding Protein alpha Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000096:biosynthesis*; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009270:Naloxone / Q000378:metabolism / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D037342:Pertussis Toxin; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D011957:Receptors, Opioid / Q000096:biosynthesis*; D010566:Virulence Factors, Bordetella / Q000378:metabolism / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D044482:Benzeneacetamides; D044385:GTP-Binding Protein alpha Subunits; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D010566:Virulence Factors, Bordetella; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; C045444:U 69593