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利德尔综合征突变增加人类上皮钠通道活性的机制。

Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.

作者信息

Snyder P M, Price M P, McDonald F J, Adams C M, Volk K A, Zeiher B G, Stokes J B, Welsh M J

机构信息

Howard Hughes Medical Institute, University of Iowa College of Medicine Iowa City 52242, USA.

出版信息

Cell. 1995 Dec 15;83(6):969-78. doi: 10.1016/0092-8674(95)90212-0.

Abstract

Liddle's syndrome is an inherited form of hypertension caused by mutations that truncate the C-terminus of human epithelial Na+ channel (hENaC) subunits. Expression of truncated beta and gamma hENaC subunits increased Na+ current. However, truncation did not alter single-channel conductance or open state probability, suggesting there were more channels in the plasma membrane. Moreover, truncation of the C-terminus of the beta subunit increased apical cell-surface expression of hENaC in a renal epithelium. We identified a conserved motif in the C-terminus of all three subunits that, when mutated, reproduced the effect of Liddle's truncations. Further, both truncation of the C-terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C-terminus of beta hENaC. Thus, by deleting a conserved motif, Liddle's mutations increase the number of Na+ channels in the apical membrane, which increases renal Na+ absorption and creates a predisposition to hypertension.

摘要

利德尔综合征是一种遗传性高血压,由截断人类上皮钠通道(hENaC)亚基C末端的突变引起。截短的β和γ hENaC亚基的表达增加了钠电流。然而,截短并未改变单通道电导或开放状态概率,这表明质膜中有更多的通道。此外,β亚基C末端的截短增加了肾上皮细胞中hENaC的顶端细胞表面表达。我们在所有三个亚基的C末端鉴定出一个保守基序,当该基序发生突变时,会重现利德尔截短的效应。此外,C末端的截短和保守C末端基序的突变均增加了含有β hENaC C末端的嵌合蛋白的表面表达。因此,通过删除一个保守基序,利德尔突变增加了顶端膜中钠通道的数量,从而增加了肾脏对钠的重吸收,并导致易患高血压。

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