Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle

George Gallos, Kenneth E. Remy, Jennifer Danielsson, Hiromi Funayama, Xiao Wen Fu, Herng Yu Sucie Chang, Peter Yim, Dingbang Xu, Charles W. Emala

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma.

Original languageEnglish
Pages (from-to)L625-L634
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume305
Issue number9
DOIs
StatePublished - Nov 1 2013

Keywords

  • Airway smooth muscle
  • Electrophysiology
  • Immunohistochemistry
  • MQAE
  • RT-PCR

Fingerprint

Dive into the research topics of 'Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle'. Together they form a unique fingerprint.

Cite this