Investigators have found that bronchodilatory β-adrenergic receptor (βAR) agonists induce relaxation of airway smooth muscle via both cAMP-dependent and -independent mechanisms, possibly indicating other roles for cAMP signaling. Bogard et al. have investigated the signaling of adenylyl cyclase (AC) isoforms AC2, AC3, and AC6 in mouse bronchial smooth muscle cells. Given that the AC isoform expression profile largely determines the compartments in which cAMP is generated, and that the mouse airway smooth-muscle AC expression profile differs significantly from that of humans, it is suggested that mouse models of airway function regulated by G protein-coupled receptor (GPCR)-AC pathways may not accurately reflect responses in humans. Nonetheless, it is clear that airway smooth muscle signaling is highly compartmentalized at proximal steps (GPCR and AC), lipid rafts/caveolae acting as sites for βAR-AC5/6 signalosomes and nonraft membranes serving as sites for prostacyclin EP2 receptor-AC2 signalosomes. cAMP regulation of cytoskeletal reorganization, a more distal event, is also compartmentalized, with phosphodiesterase (PDE), particularly PDE4, activity required for maintaining the observed compartmentation. Therapies that take advantage of these distinct signaling complexes to more specifically alter bronchodilation would represent exciting new treatment modalities.
See article at J Pharmacol Exp Ther 2012, 342:586–595.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics