Functional coupling of V-ATPase and CLC-5.
Functional coupling of V-ATPase and CLC-5.
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DOI：
10.5527/wjn.v6.i1.14
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发表时间：
2017-01-06
期刊：
影响因子：
--
通讯作者：
Moriya K
中科院分区：
文献类型：
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作者：
Satoh N;Suzuki M;Nakamura M;Suzuki A;Horita S;Seki G;Moriya K
登特氏病是一种X连锁肾小管病变，以低分子蛋白尿、高钙尿和进行性肾功能衰竭为特征。疾病的病因学与CLCN5基因的突变有关，该基因编码的是产生电的2Cl-/H+逆向转运体氯通道5(ClC-5)，该基因表达于具有空泡型H+-ATPase(V-ATPase)的肾近端小管的顶端内吞体内。ClC-5最初被认为是ClC-通道家族中的一员，被认为是将Cl-分流到内体腔内，通过V-ATPase分散H+积累，从而促进有效的内体酸化。然而，最近的发现表明ClC-5实际上不是一个氯-通道，而是一个2Cl-/H+逆向转运体，挑战了这一经典的分流模型，导致了对其生理作用的新一轮激烈辩论。通过ClC-5积累的氯被预测在内吞作用中起关键作用，正如携带人工氯通道突变E211A的小鼠所说明的那样，该突变发生了有缺陷的内吞作用，但内体酸化正常。相反，最近对一例典型Dent病患者中新发现的致病氯通道突变E211Q的功能分析证实了V-ATPase和ClC-5在内体酸化中的功能偶联，支持经典的分流模型。在这篇社论中，我们将讨论目前对ClC-5的生理作用的认识，特别关注V-ATPase和ClC-5的功能偶联。
Dent’s disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl-/H+ antiporter chloride channel 5 (CLC-5), which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H+-ATPase (V-ATPase). Initially identified as a member of the CLC family of Cl- channels, CLC-5 was presumed to provide Cl- shunt into the endosomal lumen to dissipate H+ accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl- channel but a 2Cl-/H+ antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl- channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl- channel mutation E211Q in a patient with typical Dent’s disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.