Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC).
Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC).
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DOI：
10.1016/bs.ctm.2018.07.005
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发表时间：
2018
影响因子：
--
通讯作者：
Qiu Z
中科院分区：
文献类型：
--
作者：
Osei-Owusu J;Yang J;Vitery MDC;Qiu Z
体积调节阴离子通道(Vrac)由细胞肿胀激活，在细胞体积调节中起关键作用。Vrac在脊椎动物细胞中广泛表达，还参与许多其他生理和细胞过程，包括液体分泌、谷氨酸释放、膜电位调节、细胞增殖、迁移和凋亡。虽然vrac的生物物理性质已经得到了很好的表征，但近三十年来，vrac的分子身份仍然是一个谜。最近的发现改变了这个领域，这些发现表明，富含亮氨酸重复序列的蛋白8A(LRRC8A，也称为SWELL1)及其其他四个同源物形成了异构体vrac通道。LRRC8亚基的组成决定了多种不同VRAC的通道特性和底物选择性。将纯化的含有SWELL1的蛋白质复合体掺入脂双层中足以重建通道活性，这一发现支持细胞内离子强度的降低是细胞肿胀期间vrac激活的机制。Swell1基因敲除小鼠的特征揭示了vrac在T细胞发育、胰腺β细胞葡萄糖刺激的胰岛素分泌和脂肪细胞代谢功能中的重要作用。渗透有机渗透剂和代谢物的能力是vrac的一大特点。预计vrac底物的清单将会增加，现在还包括一些抗癌药物和抗生素，即使在非细胞肿胀的条件下也是如此。因此，vrac在耐药和细胞间通讯中的重要作用正在显现。本文综述了vrac的结构-功能关系和生理学方面的最新进展，并讨论了未来需要解决的关键问题。
The Volume-Regulated Anion Channel (VRAC) is activated by cell swelling and plays a key role in cell volume regulation. VRAC is ubiquitously expressed in vertebrate cells and also implicated in many other physiological and cellular processes including fluid secretion, glutamate release, membrane potential regulation, cell proliferation, migration, and apoptosis. Although its biophysical properties have been well characterized, the molecular identity of VRAC remained a mystery for almost three decades. The field was transformed by recent discoveries showing that the leucine-rich repeat-containing protein 8A (LRRC8A, also named SWELL1) and its four other homologs form heteromeric VRAC channels. The composition of LRRC8 subunits determines channel properties and substrate selectivity of a large variety of different VRACs. Incorporating purified SWELL1-containing protein complexes into lipid bilayers is sufficient to reconstitute channel activities, a finding that supports the decrease in intracellular ionic strength as the mechanism of VRAC activation during cell swelling. Characterization of Swell1 knockout mice uncovers the important role of VRAC in T cell development, pancreatic β-cell glucose-stimulated insulin secretion, and adipocyte metabolic function. The ability to permeate organic osmolytes and metabolites is a major feature of VRAC. The list of VRAC substrates is expected to grow, now also including some cancer drugs and antibiotics even under non-cell swelling conditions. Therefore, a critical role of VRAC in drug resistance and cell–cell communication is emerging. This review summarizes the exciting recent progress on the structure-function relationship and physiology of VRAC and discusses key future questions to be solved.
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影响因子：
16.6
作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
通讯作者：
Brough D
DOI：
10.1073/pnas.1415739112
发表时间：
2015-02-17
影响因子：
11.1
作者：
Catalan, Marcelo A.;Kondo, Yusuke;Melvin, James E.
通讯作者：
Melvin, James E.
影响因子：
5
作者：
Best, L;Yates, AP;Nilius, B
通讯作者：
Nilius, B
影响因子：
8.2
作者：
Alibrahim, Ammar;Zhao, Li-yan;Sun, Hong-shuo
通讯作者：
Sun, Hong-shuo
影响因子：
64.8
作者：
Deneka, Dawid;Sawicka, Marta;Dutzler, Raimund
通讯作者：
Dutzler, Raimund