Gi-mediated stimulation of type II adenylyl cyclase is augmented by Gq- coupled receptor activation and phorbol ester treatment

• Published in: The Journal of neuroscience Vol. 16; no. 4; pp. 1317 - 1323
• Main Authors: Tsu, RC, Wong, YH
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15.02.1996; Society for Neuroscience
• Subjects: Adenylyl Cyclases - drug effects; Cell Line; Cyclic AMP - metabolism; Dopamine - metabolism; GTP-Binding Proteins - physiology; Humans; Models, Molecular; Phorbol Esters - pharmacology; Signal Transduction - drug effects
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.16-04-01317.1996

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.