Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine
Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine
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DOI：
10.1007/s00424-014-1559-2
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发表时间：
2015-06-01
影响因子：
4.5
通讯作者：
Kunzelmann, Karl
中科院分区：
文献类型：
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作者：
Schreiber, Rainer;Faria, Diana;Kunzelmann, Karl
肠上皮电解质分泌被细胞内cAMP或Ca2+的增加和顶端Cl-通道的打开所激活。在婴幼儿和幼龄动物中，Ca2+激活的氯离子通道可能在轮状病毒感染期间引起分泌性腹泻，而不是在成人中。虽然对camp激活的囊性纤维化跨膜传导调节因子（CFTR）通道的贡献有详细的了解，但通过鉴定anoctamin （TMEM16）蛋白家族，分析Ca2+依赖性Cl-通道的作用成为可能。我们在小鼠小肠和大肠中证实了几种氨基酸亲缘物的表达。通过肠道特异性敲除anoctamin 1 （Ano1）和anoctamin 10 （Ano10）的小鼠模型以及anoctamin 6 （Ano6）的常规敲除模型，我们证明了anoctamin在由毒菌碱激动剂carbachol （CCH）诱导的Ca2+依赖性Cl-分泌中的作用。Ano1在回肠和大肠中优先表达，在那里它支持Ca2+激活的Cl-分泌。相反，在空肠中，Ano10是Ca2+依赖性Cl-分泌所必需的，在空肠中没有检测到Ano1的表达。虽然广泛表达，但Ano6在肠胆碱能Cl-分泌中没有作用。Ano1位于基底外侧腔室/膜上，而不是在根尖膜上，在根尖膜上它支持cch诱导的Ca2+增加，而根尖Cl-通道的基本和可能唯一的是CFTR。这些结果确定了Ano1在肠道Ca2+依赖性Cl-分泌中的新作用，并首次证明了Ano10对肠道运输的贡献。
Intestinal epithelial electrolyte secretion is activated by increase in intracellular cAMP or Ca2+ and opening of apical Cl- channels. In infants and young animals, but not in adults, Ca2+-activated chloride channels may cause secretory diarrhea during rotavirus infection. While detailed knowledge exists concerning the contribution of cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) channels, analysis of the role of Ca2+-dependent Cl- channels became possible through identification of the anoctamin (TMEM16) family of proteins. We demonstrate expression of several anoctamin paralogues in mouse small and large intestines. Using intestinal-specific mouse knockout models for anoctamin 1 (Ano1) and anoctamin 10 (Ano10) and a conventional knockout model for anoctamin 6 (Ano6), we demonstrate the role of anoctamins for Ca2+-dependent Cl- secretion induced by the muscarinic agonist carbachol (CCH). Ano1 is preferentially expressed in the ileum and large intestine, where it supports Ca2+-activated Cl- secretion. In contrast, Ano10 is essential for Ca2+-dependent Cl- secretion in jejunum, where expression of Ano1 was not detected. Although broadly expressed, Ano6 has no role in intestinal cholinergic Cl- secretion. Ano1 is located in a basolateral compartment/membrane rather than in the apical membrane, where it supports CCH-induced Ca2+ increase, while the essential and possibly only apical Cl- channel is CFTR. These results define a new role of Ano1 for intestinal Ca2+-dependent Cl- secretion and demonstrate for the first time a contribution of Ano10 to intestinal transport.