Adenylyl cyclase type-VIII activity is regulated by G(betagamma) subunits

Cell Signal. 2006 Jan;18(1):62-8. doi: 10.1016/j.cellsig.2005.03.014. Epub 2005 May 31.


The Ca2+-activated adenylyl cyclase type VIII (AC-VIII) has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. It has not been clear whether Gi/o proteins and G-protein coupled receptors regulate the activity of AC-VIII. Here we show in intact mammalian cell system that AC-VIII is inhibited by mu-opioid receptor activation and that this inhibition is pertussis toxin sensitive. Moreover, we show that G(betagamma) subunits inhibit AC-VIII activity, while constitutively active alphai/o subunits do not. Different Gbeta isoforms varied in their efficacies, with Gbeta1gamma2 or Gbeta2gamma2 being more efficient than Gbeta3gamma2 and Gbeta4gamma2, while Gbeta5 (transfected with gamma2) had no effect. As for the Ggamma subunits, Gbeta1 inhibited AC-VIII activity in the presence of all gamma subunits tested except for gamma5 that had only a marginal activity. Moreover, cotransfection with proteins known to serve as scavengers of Gbetagamma dimers, or to reduce Gbetagamma plasma membrane anchorage, markedly attenuated the mu-opioid receptor-induced inhibition of AC-VIII. These results demonstrate that Gbetagamma (originating from agonist activation of these receptors) and probably not Galphai/o subunits are involved in the agonist inhibition of AC-VIII.

Publication types

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

MeSH terms

  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Colforsin / pharmacology
  • Dimerization
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein beta Subunits / pharmacology*
  • GTP-Binding Protein gamma Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / pharmacology*
  • Ionomycin / pharmacology
  • Morphine / pharmacology
  • Pertussis Toxin / pharmacology
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism


  • Adenylyl Cyclase Inhibitors
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Receptors, Opioid, mu
  • Colforsin
  • Ionomycin
  • Morphine
  • Pertussis Toxin
  • Adenylyl Cyclases
  • adenylyl cyclase 8