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Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity.
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ABSTRACT: Background and purpose
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.Experimental approach
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-IP?). Effects on Ca²? sensitivity were assessed on lung slices treated with caffeine and ryanodine to permeabilize ASM cells to Ca²? .Key results
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-IP? were also attenuated by chloroquine, quinine and denotonium. In Ca²?-permeabilized ASM cells, the TAS2R10 agonists dilated MCh- and 5HT-constricted airways.Conclusions and implications
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 IP? receptors. Further characterization of bronchodilatory TAS2R agonists may lead to the development of novel therapies for the treatment of bronchoconstrictive conditions.
SUBMITTER: Tan X
PROVIDER: S-EPMC3969078 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
Publications
Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity.
British journal of pharmacology 20140201 3
<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Airways in mouse lung slices were contracted with either ...[more]