Regulation of Adenylyl Cyclase Type V/VI in Smooth Muscle: Interplay of Inhibitory G Protein and Ca2+ Influx

• Published in: Molecular pharmacology 1998-07, Vol.54 (1), p.122-128
• Main Authors: Murthy, K S, Makhlouf, G M
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Adenylyl Cyclases - metabolism; Animals; Calcium - metabolism; Colforsin - pharmacology; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; GTP-Binding Proteins - antagonists & inhibitors; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; Muscle, Smooth - enzymology; Rabbits; Stomach - enzymology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.54.1.122

The characteristics of inhibitory regulation of adenylyl cyclase V/VI by Ca 2+ 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 P 2X receptors, was abolished by zero Ca 2+ , whereas inhibition by UTP, which activates P 2Y2 receptors coupled to G q/11 and G i3 , was not affected by zero Ca 2+ but was abolished by pertussis toxin (PTX). Inhibition by ATP, which activates both P 2X and P 2Y2 receptors, was not affected by zero Ca 2+ alone; but after inhibition mediated by G αi3 was blocked with PTX, inhibition by Ca 2+ influx was unmasked and was abolished by zero Ca 2+ . Inhibition by cholecystokinin-8 was observed only during the phase of capacitative Ca 2+ influx and was blocked by zero Ca 2+ . Inhibition by UTP during this phase was not affected by zero Ca 2+ alone; but after inhibition mediated by Gα i3 was blocked with PTX, inhibition by Ca 2+ influx was unmasked and was abolished by zero Ca 2+ . Inhibition of adenylyl cyclase V/VI activity in smooth muscle can be mediated independently by inhibitory G proteins and Ca 2+ influx but is exclusively mediated by inhibitory G proteins when both mechanisms are triggered.