Voltage-gated sodium channels assemble and gate as dimers.
Voltage-gated sodium channels assemble and gate as dimers.
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DOI：
10.1038/s41467-017-02262-0
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发表时间：
2017-12-12
影响因子：
16.6
通讯作者：
Deschênes I
中科院分区：
文献类型：
--
作者：
Clatot J;Hoshi M;Wan X;Liu H;Jain A;Shinlapawittayatorn K;Marionneau C;Ficker E;Ha T;Deschênes I
电压门控钠通道的快速打开和关闭对于动作电位通过可兴奋组织的正确传播至关重要。与钾通道不同，钠通道α亚基被认为形成功能单体。然而，越来越多的文献显示与单一α亚基作为单体发挥作用的传统观点不一致。在这里，我们证明了钠通道α亚基不仅在物理上相互作用，而且它们实际上作为二聚体组装，功能和门控。我们确定了参与二聚化的区域，并证明14-3-3蛋白介导了偶联门控。重要的是，我们在哺乳动物钠通道中显示了这种机制的保守性。我们的研究不仅改变了钠通道组装、结构和功能的传统范式，而且重要的是，这一发现涉及通道二聚化和生物物理耦合的机制，可以为治疗和/或预防钠通道病的新方法和靶点打开大门。电压门控钠通道在可兴奋组织中表达，突变与心律失常和通道病有关。在这里，作者表明钠通道α亚基相互作用形成二聚体，并作为二聚体进行门控，并且这种功能性二聚化是保守的。
Fast opening and closing of voltage-gated sodium channels are crucial for proper propagation of the action potential through excitable tissues. Unlike potassium channels, sodium channel α-subunits are believed to form functional monomers. Yet, an increasing body of literature shows inconsistency with the traditional idea of a single α-subunit functioning as a monomer. Here we demonstrate that sodium channel α-subunits not only physically interact with each other but they actually assemble, function and gate as a dimer. We identify the region involved in the dimerization and demonstrate that 14-3-3 protein mediates the coupled gating. Importantly we show conservation of this mechanism among mammalian sodium channels. Our study not only shifts conventional paradigms in regard to sodium channel assembly, structure, and function but importantly this discovery of the mechanism involved in channel dimerization and biophysical coupling could open the door to new approaches and targets to treat and/or prevent sodium channelopathies. Voltage-gated sodium channels are expressed in excitable tissues and mutations have been linked to cardiac arrhythmias and channelopathies. Here the authors show that the sodium channel α-subunits interact to form a dimer and gate as dimer and that this functional dimerisation is conserved.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
5.5
作者：
Shinlapawittayatorn, Krekwit;Du, Xi X.;Liu, Haiyan;Ficker, Eckhard;Kaufman, Elizabeth S.;Deschenes, Isabelle
通讯作者：
Deschenes, Isabelle
DOI：
10.1073/pnas.1106363108
发表时间：
2011-05-31
影响因子：
11.1
作者：
Liebeskind, Benjamin J.;Hillis, David M.;Zakon, Harold H.
通讯作者：
Zakon, Harold H.
影响因子：
4.8
作者：
Masters, SC;Fu, H
通讯作者：
Fu, H
影响因子：
56.9
作者：
Shen, Huaizong;Zhou, Qiang;Yan, Nieng
通讯作者：
Yan, Nieng