Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada.
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada.
Nat Commun. 2018 Oct 24;9(1):4417. doi: 10.1038/s41467-018-06859-x.
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 是一种主要的电压门控钾通道，它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包含 Kv1.2 的多蛋白复合物，然后筛选对 Kv1.2 的影响。我们报告称，中性氨基酸转运蛋白 Slc7a5 对 Kv1.2 有深远的影响。与 Slc7a5 共表达会减少总 Kv1.2 蛋白，并使激活的电压依赖性显著超极化至-47 mV。这些效应通过表达 Slc3a2 而减弱，Slc3a2 是 Slc7a5 的已知结合伴侣。Slc7a5 介导的电流抑制作用的部分原因是门控效应的组合，包括加速失活和通道激活的超极化移位，导致通道积累在非传导状态。最近报道的与神经发育迟缓相关的两个 Slc7a5 突变体表现出定位缺陷，并对 Kv1.2 的作用减弱。此外，癫痫相关的功能获得性 Kv1.2 突变体对 Slc7a5 的敏感性增强。
