Gi-mediated stimulation of type II adenylyl cyclase is augmented by Gq-coupled receptor activation and phorbol ester treatment.
Synergism between Gs- and Gi- or Gq-dependent signaling pathways has been demonstrated in the stimulation of type II adenylyl cyclase (AC-II). Provision of activated alpha s is known to allow numerous Gi-coupled receptors to stimulate AC-II and to potentiate the responses to Gq-coupled receptors. To explore possible interactions between Gi- and Gq-coupled receptors that are independent of alpha s, the activity of AC-II was determined after the activation of Gi- and Gq-regulated pathways. Human embryonic kidney 293 cells were transiently cotransfected with cDNAs encoding AC-II and various G-protein-coupled receptors. Agonist-bound Gi-coupled receptors (including the formyl peptide, dopamine-D2, and delta-opioid receptors) stimulated AC-II activity in the absence of activated alpha s, provided that the cells were treated with 100 nM phorbol 12-myristate 13-acetate. Activation of protein kinase C (PKC) thus appears to relieve the requirement for the presence of activated alpha s. Stimulation of PKC via Gq-coupled receptors also allowed Gi-coupled receptors to activate AC-II. Coexpression of the m1 muscarinic receptor with the dopamine-D2 receptor permitted dopamine to stimulate AC-II in the presence of carbachol. The phorbol ester-permissive and alpha s-independent stimulation was mediated by G-protein beta gamma subunits because it was blocked by the beta gamma scavengers alpha t and beta-adrenergic receptor kinase. These results show that AC-II can efficiently integrate signals generated by Gq- and Gi-coupled receptors via a mechanism that is independent of Gs.
Tsu
R C
RC
Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon.
Wong
Y H
YH
D000262:Adenylyl Cyclases / Q000187:drug effects*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D010703:Phorbol Esters / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D010703:Phorbol Esters; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D004298:Dopamine