Intestinal TMEM16A control luminal chloride secretion in a NHERF1 dependent manner

TMEM16A (Transmembrane protein 16A or Anoctamin1) is a calcium-activated chloride channel. (CaCC),that exerts critical roles in epithelial secretion. However, its localization, function, and regulation in intestinal chloride (Cl−) secretion remain obscure. Here, we show that TMEM16A protein abundanc...

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Bibliographic Details
Published in:Biochemistry and biophysics reports 2021-03, Vol.25, p.100912-100912, Article 100912
Main Authors: Saha, Tultul, Aoun, Joydeep, Hayashi, Mikio, Ali, Sheikh Irshad, Sarkar, Paramita, Bag, Prasanta Kumar, Leblanc, Normand, Ameen, Nadia, Woodward, Owen M., Hoque, Kazi Mirajul
Format: Article
Language:English
Subjects:
Ano1
Cystic fibrosis
Intestine
NHERF1
Secretion
TMEM16A
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Summary:TMEM16A (Transmembrane protein 16A or Anoctamin1) is a calcium-activated chloride channel. (CaCC),that exerts critical roles in epithelial secretion. However, its localization, function, and regulation in intestinal chloride (Cl−) secretion remain obscure. Here, we show that TMEM16A protein abundance correlates with Cl− secretion in different regions of native intestine activated by the Ca2+-elevating muscarinic agonist carbachol (CCH). Basal, as well as both cAMP- and CCH-stimulated Isc, was largely reduced in Ano1 ± mouse intestine. We found CCH was not able to increase Isc in the presence of apical to serosal Cl− gradient, strongly supporting TMEM16A as primarily a luminal Cl− channel. Immunostaining demonstrated apical localization of TMEM16A where it colocalized with NHERF1 in mouse colonic tissue. Cellular depletion of NHERF1 in human colonic T84 cells caused a significant reduction of both cAMP- and CCH-stimulated Isc. Immunoprecipitation experiments revealed that NHERF1 forms a complex with TMEM16A through a PDZ-based interaction. We conclude that TMEM16A is a luminal Cl− channel in the intestine that functionally interacts with CFTR via PDZ-based interaction of NHERF1 for efficient and specific cholinergic stimulation of intestinal Cl− secretion. •TMEM16A express apically and operate Cl− secretion in mouse intestinal tissue.•TMEM16A potentially interacts with NHERF1 via its C-terminal PDZ binding motif.•TMEM16A-NHERF1 complex is requisite for cAMP and Ca2+ mediated apical Cl− secretion.
ISSN:2405-5808
2405-5808
DOI:10.1016/j.bbrep.2021.100912