S1-S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation.
S1-S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation.
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DOI：
10.1085/jgp.201210935
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Winston V
中科院分区：
文献类型：
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作者：
Groome JR;Winston V
带正电荷的S4片段通过电场的运动驱动离子通道的电压依赖性门控。对原核钠通道的研究提供了S1和S2段带负电残基与S4段带正电残基的静电相互作用促进激活的机制。在哺乳动物钠通道中，S4片段促进区域特异性功能，包括激活和几种形式的失活。我们测试了S1-S3反电荷调节真核钠通道功能的想法，包括快速失活。利用细菌通道提供的结构数据，我们构建了哺乳动物骨骼肌钠通道hNaV1.4各结构域的S1-S4电压传感器模块（VSM）的同源模型。这些结果表明，hNaV1.4中假定的反荷侧链是朝向S4的正电荷补体的。我们使用诱变来定义细胞外负电荷簇（ENC）、疏水电荷区（HCR）和细胞内负电荷簇（INC）中保守残基的作用。在I-III结构域，电荷反转的VSM突变抑制了激活。ENC结构域III （E1051R, D1069K）和IV （E1373K, N1389K）中的电荷反转通过降低其概率、减慢进入速度和加速恢复来稳定快速失活。一些INC突变增加了闭合状态的失活，减缓了恢复。我们的研究结果将VSM反电荷的功能表征扩展到快速失活，并支持这些残基在哺乳动物钠通道的域特异性门控转变中起关键作用的前提。
The movement of positively charged S4 segments through the electric field drives the voltage-dependent gating of ion channels. Studies of prokaryotic sodium channels provide a mechanistic view of activation facilitated by electrostatic interactions of negatively charged residues in S1 and S2 segments, with positive counterparts in the S4 segment. In mammalian sodium channels, S4 segments promote domain-specific functions that include activation and several forms of inactivation. We tested the idea that S1–S3 countercharges regulate eukaryotic sodium channel functions, including fast inactivation. Using structural data provided by bacterial channels, we constructed homology models of the S1–S4 voltage sensor module (VSM) for each domain of the mammalian skeletal muscle sodium channel hNaV1.4. These show that side chains of putative countercharges in hNaV1.4 are oriented toward the positive charge complement of S4. We used mutagenesis to define the roles of conserved residues in the extracellular negative charge cluster (ENC), hydrophobic charge region (HCR), and intracellular negative charge cluster (INC). Activation was inhibited with charge-reversing VSM mutations in domains I–III. Charge reversal of ENC residues in domains III (E1051R, D1069K) and IV (E1373K, N1389K) destabilized fast inactivation by decreasing its probability, slowing entry, and accelerating recovery. Several INC mutations increased inactivation from closed states and slowed recovery. Our results extend the functional characterization of VSM countercharges to fast inactivation, and support the premise that these residues play a critical role in domain-specific gating transitions for a mammalian sodium channel.
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影响因子：
3.7
作者：
Ma Z;Kong J;Kallen RG
通讯作者：
Kallen RG
影响因子：
16.2
作者：
CHAHINE, M;GEORGE, AL;HORN, R
通讯作者：
HORN, R
影响因子：
4.5
作者：
Jurkat-Rott, Karin;Holzherr, Boris;Fauler, Michael;Lehmann-Horn, Frank
通讯作者：
Lehmann-Horn, Frank
DOI：
10.1073/pnas.0806486105
发表时间：
2008-09-30
影响因子：
11.1
作者：
DeCaen, Paul G.;Yarov-Yarovoy, Vladimir;Catterall, William A.
通讯作者：
Catterall, William A.
影响因子：
16.8
作者：
通讯作者：
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