The Transmembrane Protein 16A Ca2+ activated Cl― Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

• Published in: American journal of respiratory and critical care medicine Vol. 187; no. 4; pp. 374 - 381
• Main Authors: ZHANG, Cheng-Hai, YINCHUAN LI, WEI ZHAO, LIFSHITZ, Lawrence M, HEQUAN LI, HARFE, Brian D, ZHU, Min-Sheng, RONGHUA ZHUGE
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15-02-2013
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Emergency and intensive respiratory care; Intensive care medicine; Medical sciences; airway smooth muscle; airway hyperresponsiveness; Smooth muscle; Intensive care; TMEM16A; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201207-1303OC

Rationale
: Asthma is a chronic inflammatory disorder with a characteristic of airway hyperresponsiveness (AHR). Ca
2+
-activated Cl
−
[Cl
(Ca)
] channels are inferred to be involved in AHR, yet their molecular nature and the cell type they act within to mediate this response remain unknown.
Objectives
: Transmembrane protein 16A (TMEM16A) and TMEM16B are Cl
(Ca)
channels, and activation of Cl
(Ca)
channels in airway smooth muscle (ASM) contributes to agonist-induced airway contraction. We hypothesized that
Tmem16a
and/or
Tmem16b
encode Cl
(Ca)
channels in ASM and mediate AHR.
Methods
: We assessed the expression of the TMEM16 family, and the effects of niflumic acid and benzbromarone on AHR and airway contraction, in an ovalbumin-sensitized mouse model of chronic asthma. We also cloned TMEM16A from ASM and examined the Cl
−
currents it produced in HEK293 cells. We further studied the impacts of TMEM16A deletion on Ca
2+
agonist–induced cell shortening, and on Cl
(Ca)
currents activated by Ca
2+
sparks (localized, short-lived Ca
2+
transients due to the opening of ryanodine receptors) in mouse ASM cells.
Measurements and Main Results
: TMEM16A, but not TMEM16B, is expressed in ASM cells and its expression in these cells is up-regulated in ovalbumin-sensitized mice. Niflumic acid and benzbromarone prevent AHR and contraction evoked by methacholine in ovalbumin-sensitized mice. TMEM16A produces Cl
(Ca)
currents with kinetics similar to native Cl
(Ca)
currents. TMEM16A deletion renders Ca
2+
sparks unable to activate Cl
(Ca)
currents, and weakens caffeine- and methacholine-induced cell shortening.
Conclusions
:
Tmem16a
encodes Cl
(Ca)
channels in ASM and contributes to Ca
2+
agonist–induced contraction. In addition, up-regulation of TMEM16A and its augmented activation contribute to AHR in an ovalbumin-sensitized mouse model of chronic asthma. TMEM16A may represent a potential therapeutic target for asthma.