Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel
Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel
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DOI：
10.1073/pnas.021456598
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发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Cantiello, HF
中科院分区：
文献类型：
--
作者：
González-Perrett, S;Kim, K;Cantiello, HF
多囊蛋白-2是一种普遍存在的功能未知的跨膜糖蛋白，其缺陷是常染色体显性多囊肾病（ADPKD）的主要原因，其表现是在靶器官中形成充满液体的囊肿。在这里，我们证明了多囊蛋白-2存在于人类合胞滋养细胞中，在那里它作为一个非选择性阳离子通道。polycytin -2阳性的人合胞滋养细胞尖膜脂质双分子层重构显示出具有多个亚电导状态的非选择性阳离子通道，以及对Ca2+的高选择性。该通道被抗多囊素-2抗体、Ca2+、La3+、Gd3+和利尿剂氨酰抑制。通过多囊蛋白-2异源感染Sf9昆虫细胞的膜片夹持实验，证实了多囊蛋白-2的通道功能。此外，纯化的昆虫细胞衍生的重组多囊蛋白-2和体外翻译的人多囊蛋白-2具有相似的离子通道活性。多囊蛋白-2通道可能与靶上皮（包括胎盘）的液体积聚和/或离子转运调节有关。该通道的失调为ADPKD的发生和发展提供了一种机制。
Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high permselectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD.