Adenylyl cyclase type II activity is regulated by two different mechanisms: implications for acute and chronic opioid exposure.
Acute and chronic activation of opioid receptors differentially regulate the activity of the various adenylyl cyclase (AC) isoforms. In several AC isoforms (I, V, VI and VIII) acute opioid activation (by agonists such as morphine) leads to AC inhibition, while prolonged opioid activation leads to increase in AC activity, a phenomenon known as AC sensitization or superactivation. In several other AC isoforms (II, IV and VII), acute opioid activation leads to AC stimulation, while chronic opioid exposure inhibits AC activity, in a process, which in analogy to the term "superactivation" is referred to as "superinhibition". AC-II is highly regulated by multiple and independent biochemical stimuli, including Gbetagamma, Galphas and PKC activation. We investigated the regulation of AC-II by Galphas and by PKC under conditions of acute and chronic exposure to opioid agonists in COS-7 transfected cells. We found that acute opioid exposure led to an increase in AC-II activity by either Galphas or PKC stimulation. This effect seems to be regulated by Gbetagamma subunits, in both activation pathways, as the increase in AC-II activity was abolished by pertussis toxin treatment and by Gbetagamma scavengers. On the other hand, while chronic opioid exposure led to a decrease in AC-II activity ("superinhibition") upon stimulation of the Galphas pathway, this superinhibition was not observed when the opioid treated cells were stimulated via PKC activation.
Department of Neurobiology, The Weizmann Institute of Science, Hertzel str, Rehovot 76100, Israel.
Ester
E
Schallmach
Debora
D
Steiner
Zvi
Z
Vogel
D000225:Adenine / Q000493:pharmacokinetics; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells / Q000187:drug effects; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013972:Thyrotropin / Q000494:pharmacology; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics
D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D011989:Receptors, Thyrotropin; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; C032975:12-O-tetradeca-2,4,6,8-tetranoylphorbol-13-acetate; D009020:Morphine; D013972:Thyrotropin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2; D000225:Adenine; D013755:Tetradecanoylphorbol Acetate