Inflammatory Mediators Mediate Airway Smooth Muscle Contraction through a GPCR-TMEM16A-VDCC Axis and Contribute to Bronchial Hyperresponsiveness in Asthma

Publication date: Available online 25 July 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Pei Wang, Wei Zhao, Jie Sun, Tao Tao, Xin Chen, Yan-Yan Zheng, Cheng-Hai Zhang, Zhong Chen, Yun-Qian Gao, Fan She, Ye-Qiong Li, Li-Sha Wei, Ping Lu, Cai-Ping Chen, Ji Zhou, Da-Quan Wang, Liang Chen, Xiao-Hao Shi, Linhong Deng, Ronghua ZhuGe, Hua-Qun Chen, Min-Sheng Zhu
BackgroundAllergic inflammation has long been implicated in asthmatic hyperresponsiveness of airway smooth muscle (ASM), but its mechanism underlying remains incompletely understood. Serving as GPCR agonists, several inflammatory mediators can induce membrane depolarization, contract ASM and augment cholinergic contractile response. We hypothesized that the signal cascade integrating on membrane depolarization by the mediators might involve asthmatic hyperresponsiveness.ObjectiveWe sought to investigate the signalling transduction of inflammatory mediators in ASM contraction and assess its contribution in the genesis of hyperresponsiveness.MethodsWe assessed the capacity of inflammatory mediators to induce depolarization currents by electrophysiological analysis. We analysed the phenotypes of TMEM16A knockout mice, applied pharmacological reagents and measured the Ca²⁺ signal during ASM contraction. To study the role of the depolarization signalling in asthmatic hyperresponsiveness, we measured the synergistic contraction by acetylcholine and inflammatory mediators both ex vivo and in OVA-induced mouse modelResultsInflammatory mediators, such as 5-HT, histamine, U46619 and LTD4, are capable of inducing ClCa currents in ASM cells, and these currents are mediated by TMEM16A. A combination of multiple analysis revealed that a GPCR-TMEM16A-VDCC signalling axis was required for ASM contraction induced by inflammatory mediators. Block of TMEM16A activity may significantly inhibit the synergistic contraction of acetylcholine and the mediators, and hence reduces hypersensitivity.ConclusionsA GPCR-TMEM16A-VDCC axis contributes to inflammatory mediator-induced ASM contraction, and synergistically activating TMEM16A by allergic inflammatory mediators with cholinergic stimuli.

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Teaser

The GPCR-TMEM16A-VDCC signalling axis plays important role in inflammatory mediator-induced ASM contraction and hypersensitivity. TMEM16A may be a prospective drug target of asthma.


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