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

Abstract

Synergism between Gs- and G1- or Gq-dependent signaling pathways has been demonstrated in the stimulation of type II adenylyl cyclase (AC-II). Provision of activated αs is known to allow numerous G1-coupled receptors to stimulate AC-II and to potentiate the responses to Gq-coupled receptors. To explore possible interactions between G1- and Gq-coupled receptors that are independent of αs, the activity of AC-II was determined after the activation of G1- and Gq-reguiated pathways. Human embryonic kidney 293 cells were transiently cotransfected with cDNAs encoding AC-II and various G-protein-coupled receptors. Agonist-bound G1-coupled receptors (including the formyl peptide, dopamine-D2, and δ-opioid receptors) stimulated AC-II activity in the absence of activated αs, 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 αs. Stimulation of PKC via Gq-coupled receptors also allowed G1-coupled receptors to activate AC-II. Coexpression of the m1 muscarinic receptor with the dopamine-D2 receptor permitted dopamineto stimulate AC-II in the presence of carbachol. The phorbol esterpermissive and αs-independent stimulation was mediated by G-protein βγ subunits because it was blocked by the βγ scavengers α1 and β-adrenergic receptor kinase. These results show that AC-II can efficiently integrate signals generated by Gq- and G1-coupled receptors via a mechanism that is independent of Gs.