壁细胞的胃酸分泌由微管泡中的钙外流通道介导。
Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca Efflux Channel in the Tubulovesicle.
作者信息
Sahoo Nirakar, Gu Mingxue, Zhang Xiaoli, Raval Neel, Yang Junsheng, Bekier Michael, Calvo Raul, Patnaik Samarjit, Wang Wuyang, King Greyson, Samie Mohammad, Gao Qiong, Sahoo Sasmita, Sundaresan Sinju, Keeley Theresa M, Wang Yanzhuang, Marugan Juan, Ferrer Marc, Samuelson Linda C, Merchant Juanita L, Xu Haoxing
机构信息
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
出版信息
Dev Cell. 2017 May 8;41(3):262-273.e6. doi: 10.1016/j.devcel.2017.04.003.
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca release from TV stores. Hence, we demonstrated that ML1, acting as a Ca channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.
壁细胞分泌胃酸需要富含H/K-ATP酶的微管泡（TVs）在组胺刺激下通过环磷酸腺苷升高向顶膜运输并胞吐。在此，我们发现瞬时受体电位黏脂素1（TRPML1，ML1），一种在IV型黏脂贮积症（ML-IV）中发生突变的蛋白质，是TVs胞吐和酸分泌所必需的微管泡通道。据报道，ML-IV患者胃酸缺乏，而在小鼠壁细胞中过表达ML1可诱导持续性酸分泌。ML1抑制剂和激动剂分别阻断和刺激胃酸分泌。细胞器靶向钙成像和顶膜空泡膜的直接膜片钳记录显示，ML1介导了组胺诱导的TVs钙库钙释放所需的微管泡膜上PKA激活的电导。因此，我们证明，ML1作为微管泡中的钙通道，将递质引发的环核苷酸信号与壁细胞中钙依赖的微管泡胞吐联系起来，提供了一种可作为治疗胃酸相关胃病靶点的调节机制。
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