Role of M2 muscarinic receptors in airway smooth muscle contraction

Airway smooth muscle expresses both M-2 and M-3 muscarinic receptors with the majority of the receptors of the M-2 subtype. Activation of M-3 receptors, which couple to G(q), initiates contraction of airway smooth muscle while activation of M-2 receptors, which couple to G(i), inhibits beta-adrenergic mediated relaxation. Increased sensitivity to intracellular Ca2+ is an important mechanism for agonist-induced contraction of airway smooth muscle but the signal transduction pathways involved are uncertain. We studied Ca2+ sensitization by acetylcholine (ACh) and endothelin-1 (ET-1) in porcine tracheal smooth muscle by measuring contractions at constant [Ca2+] in strips permeabilized with Staphylococcal alpha-toxin. Both ACh and ET-1 contracted airway smooth muscle at constant [Ca2+]. Pretreatment with pertussis toxin for 18-20 hours reduced ACh contractions, but had no effect on those of ET-1 or GTP gamma S. We conclude that the M-2 muscarinic receptor contributes to airway smooth muscle contraction at constant [Ca2+] via the heterotrimeric G-protein G(i).