Inhibition of AC-II activity following chronic agonist exposure is modulated by phosphorylation

J Mol Neurosci. 2006;29(2):115-22. doi: 10.1385/JMN:29:2:115.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclase Inhibitors*
  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism
  • Analgesics, Opioid / metabolism
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / metabolism
  • Enzyme Inhibitors / metabolism*
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Morphine / metabolism
  • Okadaic Acid / metabolism
  • Phosphorylation
  • Protein Kinase C / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism
  • Receptors, Thyrotropin / genetics
  • Receptors, Thyrotropin / metabolism

Substances

  • Adenylyl Cyclase Inhibitors
  • Analgesics, Opioid
  • Enzyme Inhibitors
  • Isoenzymes
  • Protein Subunits
  • Receptors, Opioid, mu
  • Receptors, Thyrotropin
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Okadaic Acid
  • Morphine
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-raf
  • Protein Kinase C
  • Heterotrimeric GTP-Binding Proteins
  • Adenylyl Cyclases
  • adenylyl cyclase 2