TY - JOUR T1 - Regulation of Adenylyl Cyclase Type V/VI in Smooth Muscle: Interplay of Inhibitory G Protein and Ca<sup>2+</sup> Influx JF - Molecular Pharmacology JO - Mol Pharmacol SP - 122 LP - 128 DO - 10.1124/mol.54.1.122 VL - 54 IS - 1 AU - Karnam S. Murthy AU - Gabriel M. Makhlouf Y1 - 1998/07/01 UR - http://molpharm.aspetjournals.org/content/54/1/122.abstract N2 - The characteristics of inhibitory regulation of adenylyl cyclase V/VI by Ca2+ and G proteins were examined in dispersed gastric smooth muscle cells. The mechanisms were evoked separately, sequentially, or concurrently using ligand-gated and G protein-coupled receptor agonists and receptor-independent probes (e.g, thapsigargin). During the initial phase of agonist stimulation, α,β-methylene-ATP, UTP, and ATP inhibited forskolin-stimulated cAMP formation in a concentration-dependent fashion. Inhibition by α,β-methylene-ATP, which activates ligand-gated P2X receptors, was abolished by zero Ca2+, whereas inhibition by UTP, which activates P2Y2 receptors coupled to Gq/11 and Gi3, was not affected by zero Ca2+ but was abolished by pertussis toxin (PTX). Inhibition by ATP, which activates both P2X and P2Y2 receptors, was not affected by zero Ca2+ alone; but after inhibition mediated by Gαi3 was blocked with PTX, inhibition by Ca2+influx was unmasked and was abolished by zero Ca2+. Inhibition by cholecystokinin-8 was observed only during the phase of capacitative Ca2+ influx and was blocked by zero Ca2+. Inhibition by UTP during this phase was not affected by zero Ca2+ alone; but after inhibition mediated by Gαi3 was blocked with PTX, inhibition by Ca2+influx was unmasked and was abolished by zero Ca2+. Inhibition of adenylyl cyclase V/VI activity in smooth muscle can be mediated independently by inhibitory G proteins and Ca2+influx but is exclusively mediated by inhibitory G proteins when both mechanisms are triggered. ER -