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Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction

Abstract

Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca2+]i) in ASM in a Gβγ–, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP3) receptor–dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca2+]i response at the cell membrane, which opens large-conductance Ca2+-activated K+ (BKCa) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

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Figure 1: Bitter tastants of diverse structures evoke increases in [Ca2+]i in human airway smooth muscle cells.
Figure 2: Bitter tastants induce relaxation of intact mouse tracheas in a non–cAMP-dependent manner.
Figure 3: Isolated airway smooth muscle responses to bitter tastants as assessed by single cell mechanics and membrane potentials.
Figure 4: Saccharin preferentially triggers localized [Ca2+]i responses in ASM cells.
Figure 5: Bitter taste receptor agonists attenuate bronchoconstriction in a mouse model of asthma.

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Acknowledgements

This work was supported by US National Heart, Lung, and Blood Institute grants HL104119 (to W.C.H.W.), HL045967 and HL071609 (to S.B.L.), HL071835 and HL075134 (to J.S.K.S.) and HL087560 (to D.A.D.).

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Authors and Affiliations

Authors

Contributions

D.A.D., single-cell mechanics and imaging, data analysis and manuscript preparation; W.C.H.W., expression studies, gene knockdown, airway physiology, data analysis and manuscript preparation; E.L.M., calcium signaling and data analysis; K.S.R., intact airway studies, expression studies, data analysis and manuscript preparation; R.M.S., airway physiology; S.S.A., single cell mechanics, data analysis, manuscript preparation; J.S.K.S., confocal calcium imaging, data analysis, manuscript preparation; S.B.L. directed all studies, data analysis and interpretation and is the primary author of the manuscript.

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Correspondence to Stephen B Liggett.

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The authors declare no competing financial interests.

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Deshpande, D., Wang, W., McIlmoyle, E. et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 16, 1299–1304 (2010). https://doi.org/10.1038/nm.2237

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