Intestinal TMEM16A control luminal chloride secretion in a NHERF1 dependent manner.
Intestinal TMEM16A control luminal chloride secretion in a NHERF1 dependent manner.
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肠TMEM16A以NHERF 1依赖性方式控制管腔氯分泌。
DOI：
10.1016/j.bbrep.2021.100912
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发表时间：
2021-03
影响因子：
2.7
通讯作者：
Hoque KM
中科院分区：
文献类型：
--
作者：
Saha T;Aoun J;Hayashi M;Ali SI;Sarkar P;Bag PK;Leblanc N;Ameen N;Woodward OM;Hoque KM
TMEM 16 A（Transmembrane protein 16 A或Anoctamin 1）是一种钙激活的氯离子通道。（CaCC），其在上皮分泌中发挥关键作用。然而，其在肠氯（Cl−）分泌中的定位、功能和调节仍然不清楚。在这里，我们发现TMEM 16 A蛋白丰度与天然肠道不同区域的Cl−分泌相关，这些区域由Ca 2+升高的毒蕈碱激动剂卡巴胆碱（CCH）激活。Ano 1 ±小鼠肠的基础Isc以及cAMP和CCH刺激的Isc均大幅降低。我们发现CCH不能在存在顶端到serum Cl−梯度的情况下增加Isc，强烈支持TMEM 16 A主要是管腔Cl−通道。免疫染色显示TMEM 16 A的顶端定位，其中它与NHERF 1在小鼠结肠组织中共定位。在人结肠T84细胞中NHERF 1的细胞耗竭引起cAMP和CCH刺激的Isc显著降低。免疫沉淀实验表明，NHERF 1通过基于PDZ的相互作用与TMEM 16 A形成复合物。我们得出结论，TMEM 16 A是肠道中的一个管腔Cl−通道，通过NHERF 1的PDZ相互作用与CFTR功能性相互作用，以有效和特异性地刺激肠道Cl−分泌。TMEM 16 A在小鼠肠组织中顶端表达并操纵Cl−分泌。TMEM 16 A可能通过其C-末端PDZ结合基序与NHERF 1相互作用。TMEM 16 A-NHERF 1复合物是cAMP和Ca 2+介导的顶端Cl−分泌所必需的。
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.
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影响因子：
2.7
作者：
He Q;Halm ST;Zhang J;Halm DR
通讯作者：
Halm DR
影响因子：
4.8
作者：
Aoun, Joydeep;Hayashi, Mikio;Hoque, Kazi Mirajul
通讯作者：
Hoque, Kazi Mirajul
DOI：
10.1152/ajpgi.00092.2018
发表时间：
2019-02-01
影响因子：
4.5
作者：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
Hoque, Kazi Mirajul