CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability.
CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability.
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CaMKII抑制减弱突变的Nav1.6通道产生的不同的功能获得效应并降低神经元的兴奋性。
DOI：
10.3390/cells11132108
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发表时间：
2022-07-04
期刊：
影响因子：
6
通讯作者：
Cummins, Theodore R.
中科院分区：
文献类型：
--
作者：
Zybura, Agnes S.;Sahoo, Firoj K.;Hudmon, Andy;Cummins, Theodore R.
异常的Nav1.6活性可诱发与癫痫相关的高兴奋性。编码Nav1.6的SCN8A基因的功能获得性突变与癫痫的发展有关；然而，介导这些变化的分子机制非常不同，可能涉及Nav1.6的翻译后调控。由于钙/钙调素依赖性蛋白激酶II （CaMKII）是Nav1.6通道的强大调节剂，我们研究了CaMKII是否调节疾病相关的Nav1.6突变体。ND7/23细胞的全细胞电压钳记录显示，CaMKII对癫痫相关突变R850Q的抑制在很大程度上再现了之前在WT Nav1.6中观察到的效果。我们还鉴定了一种罕见的错义变体R639C，它位于Nav1.6的CaMKII调制的调控热点内。预测软件算法和电生理记录显示，与WT Nav1.6相比，R639C突变体通道活性的功能增益效应包括钠电流和超极化激活的增加。重要的是，R639C突变破坏了CaMKII关键调控位点T642的磷酸化，与WT和R850Q通道不同，R639C突变对CaMKII抑制表现出明显的反应。计算模拟表明，含有R639C或R850Q突变的模型神经元具有高兴奋性，模拟CaMKII抑制对模型神经元中Nav1.6活性的影响差异降低了高兴奋性。急性CaMKII抑制可能是一种有希望的机制，可以减弱Nav1.6突变产生的功能获得效应。
Aberrant Nav1.6 activity can induce hyperexcitability associated with epilepsy. Gain-of-function mutations in the SCN8A gene encoding Nav1.6 are linked to epilepsy development; however, the molecular mechanisms mediating these changes are remarkably heterogeneous and may involve post-translational regulation of Nav1.6. Because calcium/calmodulin-dependent protein kinase II (CaMKII) is a powerful modulator of Nav1.6 channels, we investigated whether CaMKII modulates disease-linked Nav1.6 mutants. Whole-cell voltage clamp recordings in ND7/23 cells show that CaMKII inhibition of the epilepsy-related mutation R850Q largely recapitulates the effects previously observed for WT Nav1.6. We also characterized a rare missense variant, R639C, located within a regulatory hotspot for CaMKII modulation of Nav1.6. Prediction software algorithms and electrophysiological recordings revealed gain-of-function effects for R639C mutant channel activity, including increased sodium currents and hyperpolarized activation compared to WT Nav1.6. Importantly, the R639C mutation ablates CaMKII phosphorylation at a key regulatory site, T642, and, in contrast to WT and R850Q channels, displays a distinct response to CaMKII inhibition. Computational simulations demonstrate that modeled neurons harboring the R639C or R850Q mutations are hyperexcitable, and simulating the effects of CaMKII inhibition on Nav1.6 activity in modeled neurons differentially reduced hyperexcitability. Acute CaMKII inhibition may represent a promising mechanism to attenuate gain-of-function effects produced by Nav1.6 mutations.
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CAMKII将Ca2+通道的camkii tethers建立，建立了Ca2+信号的本地和专用集成商进行便利。
影响因子：
7.8
作者：
Hudmon, A;Schulman, H;Kim, J;Maltez, JM;Tsien, RW;Pitt, GS
通讯作者：
Pitt, GS
影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
影响因子：
15.9
作者：
Jarecki, Brian W.;Piekarz, Andrew D.;Cummins, Theodore R.
通讯作者：
Cummins, Theodore R.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
4.4
作者：
Berendt, Frank J.;Park, Kang-Sik;Trimmer, James S.
通讯作者：
Trimmer, James S.