Anesthetics inhibit membrane receptor coupling to the G_q/11 heterotrimeric G protein in airway smooth muscle

Background: Some anesthetics relax airway smooth muscle in part by inhibiting acetylcholine-induced increases in Ca²⁺ sensitivity, an effect associated with inhibition of guanosine nucleotide exchange at the α subunit of the G_q/11 (Gα_q/11) heterotrimeric G protein. This study tested the hypothesis that these anesthetic effects are not unique to the muscarinic receptor but are a general property of the heptahelical receptors that increase Ca²⁺ sensitivity in airway smooth muscle. Methods: Anesthetic effects on agonist-induced increases in Ca²⁺ sensitivity were measured in porcine airway smooth muscle strips permeabilized with S. aureus α-toxin. Anesthetic effects on basal (without agonist stimulation) and agonist-promoted Gα_q/11 guanosine nucleotide exchange were determined in crude membranes prepared from porcine airway smooth muscle. The nonhydrolyzable, radioactive form of guanosine 5′-triphosphate was used as the reporter for nucleotide exchange at Gα_q/11. Results: Acetylcholine, endothelin-1, and histamine caused a concentration-dependent increase in Ca²⁺ sensitivity. Halothane (0.67 ± 0.07 HIM) and hexanol (10 mM) significantly inhibited the increase in Ca²⁺ sensitivity induced by each agonist. Each agonist also caused a time- and concentration-dependent increase in Gα_q/11 nucleotide exchange. Neither anesthetic had an effect on basal Gα_q/11 nucleotide exchange, whereas halothane and hexanol significantly inhibited the increase in Gα_q/11 nucleotide exchange promoted by each agonist. Conclusion: These data suggest that inhibition of agonist-promoted guanosine nucleotide exchange at Gα_q/11 by some anesthetics may be a general property of heptahelical receptors involved cellular processes mediated by Gα_q/11, including muscarinic, endothelin-1, and histamine receptor activation of Ca²⁺ sensitivity.