Role of G proteins in agonist-induced Ca2+sensitization of tracheal smooth muscle

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Abstract
Increased sensitivity to intracellular Ca2+concentration ([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 with acetylcholine (ACh) and endothelin (ET)-1 in porcine tracheal smooth muscle by measuring contractions at a constant [Ca2+] in strips permeabilized with α-toxin or β-escin. The peptide inhibitor G protein antagonist 2A (GP Ant-2A), which has selectivity for Gqover Gi, inhibited contractile responses to ET-1, ACh, and guanosine 5′- O-(3-thiotriphosphate) (GTPγS), but the proportional inhibition of ACh responses was less than that of ET-1. Pretreatment with pertussis toxin reduced ACh contractions but had no effect on those of ET-1 or GTPγS. Clostridium botulinum C3 exoenzyme, which inactivates Rho family monomeric G proteins, caused similar reductions in contractile responses to ACh, ET-1, and GTPγS. Farnesyltransferase inhibition, which inhibits Ras G proteins, reduced responses to ET-1. We conclude that the heterotrimeric G proteins Gqand Giboth contribute to Ca2+sensitization by ACh, whereas ET-1 responses involve Gqbut not Gi. Both Gqand Gipathways likely involve Rho family small G proteins. A Ras-mediated pathway also contributes to Ca2+sensitization by ET-1 in airway smooth muscle.

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