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British journal of pharmacology

Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity.


PMID 24117140

Abstract

While selective, bitter tasting, TAS2R agonists can relax agonist-contracted airway smooth muscle (ASM), their mechanism of action is unclear. However, ASM contraction is regulated by Ca²⁺ signalling and Ca²⁺ sensitivity. We have therefore investigated how the TAS2R10 agonists chloroquine, quinine and denotonium regulate contractile agonist-induced Ca²⁺ signalling and sensitivity. Airways in mouse lung slices were contracted with either methacholine (MCh) or 5HT and bronchodilation assessed using phase-contrast microscopy. Ca²⁺ signalling was measured with 2-photon fluorescence microscopy of ASM cells loaded with Oregon Green, a Ca²⁺-sensitive indicator (with or without caged-IP₃). Effects on Ca²⁺ sensitivity were assessed on lung slices treated with caffeine and ryanodine to permeabilize ASM cells to Ca²⁺ . The TAS2R10 agonists dilated airways constricted by either MCh or 5HT, accompanied by inhibition of agonist-induced Ca²⁺ oscillations. However, in non-contracted airways, TAS2R10 agonists, at concentrations that maximally dilated constricted airways, did not evoke Ca²⁺ signals in ASM cells. Ca²⁺ increases mediated by the photolysis of caged-IP₃ were also attenuated by chloroquine, quinine and denotonium. In Ca²⁺-permeabilized ASM cells, the TAS2R10 agonists dilated MCh- and 5HT-constricted airways. TAS2R10 agonists reversed bronchoconstriction by inhibiting agonist-induced Ca²⁺ oscillations while simultaneously reducing the Ca²⁺ sensitivity of ASM cells. Reduction of Ca²⁺ oscillations may be due to inhibition of Ca²⁺ release through IP₃ receptors. Further characterization of bronchodilatory TAS2R agonists may lead to the development of novel therapies for the treatment of bronchoconstrictive conditions.