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Departments of Environmental Health Sciences and Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205
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 
-toxin or 
-escin. The peptide inhibitor G
protein antagonist 2A (GP Ant-2A), which has selectivity for
Gq over
Gi, inhibited contractile
responses to ET-1, ACh, and guanosine
5'-O-(3-thiotriphosphate) (GTP
S), 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 GTPS.
Clostridium
botulinum C3 exoenzyme, which
inactivates Rho family monomeric G proteins, caused similar reductions
in contractile responses to ACh, ET-1, and GTPS.
Farnesyltransferase inhibition, which inhibits Ras G proteins, reduced
responses to ET-1. We conclude that the heterotrimeric G proteins
Gq and
Gi both contribute to
Ca2+ sensitization by ACh, whereas
ET-1 responses involve Gq but not Gi. Both
Gq and
Gi pathways likely involve Rho
family small G proteins. A Ras-mediated pathway also contributes to
Ca2+ sensitization by ET-1 in
airway smooth muscle.
acetylcholine; airway smooth muscle contraction; endothelin; -escin; heterotrimeric G proteins
Gq and
Gi; monomeric G proteins Ras and
Rho; staphylococcal -toxin
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