Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC
Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC
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DOI：
10.1126/science.1252826
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发表时间：
2014-05-09
期刊：
影响因子：
56.9
通讯作者：
Jentsch, Thomas J.
中科院分区：
文献类型：
--
作者：
Voss, Felizia K.;Ullrich, Florian;Jentsch, Thomas J.
细胞体积的调节对许多细胞和机体功能至关重要，但其中一个关键角色——体积调节阴离子通道VRAC的分子身份仍然未知。在哺乳动物细胞中进行全基因组小干扰RNA筛选，鉴定出LRRC8A是一个VRAC成分。LRRC8A与其他LRRC8多跨膜蛋白形成异构体。LRRC8A消融VRAC电流的基因组破坏。所有五个LRRC8基因被破坏的细胞需要LRRC8A与其他LRRC8亚型共转染来重建VRAC电流。同种异构体组合决定了VRAC失活动力学。牛磺酸通量和调节体积的减少也依赖于LRRC8蛋白。我们的工作表明，VRAC定义了一类阴离子通道，表明VRAC与体积敏感的有机渗透物/阴离子通道VSOAC相同，并解释了天然VRAC电流的异质性。
Regulation of cell volume is critical for many cellular and organismal functions, yet the molecular identity of a key player, the volume-regulated anion channel VRAC, has remained unknown. A genome-wide small interfering RNA screen in mammalian cells identified LRRC8A as a VRAC component. LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. Genomic disruption of LRRC8A ablated VRAC currents. Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. The isoform combination determined VRAC inactivation kinetics. Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. Our work shows that VRAC defines a class of anion channels, suggests that VRAC is identical to the volume-sensitive organic osmolyte/anion channel VSOAC, and explains the heterogeneity of native VRAC currents.