Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations.
Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations.
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DOI：
10.1038/s41467-018-06859-x
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发表时间：
2018-10-24
影响因子：
16.6
通讯作者：
Kurata HT
中科院分区：
文献类型：
--
作者：
Baronas VA;Yang RY;Morales LC;Sipione S;Kurata HT
Kv1.2是一种重要的电压门控钾通道，影响中枢神经系统动作电位的产生和传播。我们使用质谱法探索了含有Kv1.2的多蛋白复合物，然后筛选对Kv1.2的影响。我们报告说，Slc 7a 5，一个中性氨基酸转运蛋白，对Kv1.2有深远的影响。与Slc 7a 5共表达减少了总Kv1.2蛋白，并使激活的电压依赖性显著超极化-47 mV。这些作用通过Slc 3a 2的表达而减弱，Slc 3a 2是Slc 7a 5的已知结合伴侣。深刻的Slc 7a 5介导的电流抑制部分地解释了门控效应的组合，包括加速失活和通道激活的超极化转变，导致通道在非传导状态下积累。最近报道的两个与神经发育迟缓相关的Slc 7a 5突变表现出定位缺陷，并对Kv1.2有减弱的影响。此外，癫痫相关的功能获得性Kv1.2突变体表现出对Slc 7a 5的敏感性增强。Kv1.2是一种电压门控钾通道，影响中枢神经系统中动作电位的产生和传播。在这里，作者使用电生理学，发现Slc 7a 5，一种中性氨基酸转运蛋白，对Kv1.2有着深远的影响。
Kv1.2 is a prominent voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. We explored multi-protein complexes containing Kv1.2 using mass spectrometry followed by screening for effects on Kv1.2. We report that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2. Co-expression with Slc7a5 reduces total Kv1.2 protein, and dramatically hyperpolarizes the voltage-dependence of activation by −47 mV. These effects are attenuated by expression of Slc3a2, a known binding partner of Slc7a5. The profound Slc7a5-mediated current suppression is partly explained by a combination of gating effects including accelerated inactivation and a hyperpolarizing shift of channel activation, causing channels to accumulate in a non-conducting state. Two recently reported Slc7a5 mutations linked to neurodevelopmental delay exhibit a localization defect and have attenuated effects on Kv1.2. In addition, epilepsy-linked gain-of-function Kv1.2 mutants exhibit enhanced sensitivity to Slc7a5. Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2.
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