Inhibition of AC-II activity following chronic agonist exposure is modulated by phosphorylation.
Chronic exposure to opiate agonists (followed by agonist withdrawal) leads to a large increase in the activity of adenylyl cyclase (AC) isozymes I, V, VI, and VIII, a phenomenon defined as AC superactivation (or supersensitization). On the other hand, AC isozymes belonging to the AC-II family (AC-II, AC-IV, and AC-VII) show decreased activity, referred to as superinhibition. Using COS-7 cells transiently transfected with mu-opioid receptor and AC-II, we show here that inhibition of PKC and tyrosine kinase activities synergistically reduced the level of AC-II superinhibition. Moreover, inhibitor of Raf-1 kinase also led to a decrease in AC-II superinhibition. These data suggest that Raf-1, activated by PKC and tyrosine kinase, has a role in the regulation of AC-II superinhibition.
Schallmach
Ester
E
Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Steiner
Debora
D
Vogel
Zvi
Z
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000378:metabolism; D019319:Okadaic Acid / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D021122:Protein Subunits; D017450:Receptors, Opioid, mu; D011989:Receptors, Thyrotropin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019319:Okadaic Acid; D009020:Morphine; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2