Amarillo Yimy, De Santiago-Castillo Jose A, Dougherty Kevin, Maffie Jonathon, Kwon Elaine, Covarrubias Manuel, Rudy Bernardo
Smilow Neuroscience Program, Smilow Research Center, New York University School of Medicine, 522 First Avenue, 6th Floor, New York, NY 10016, USA.
J Physiol. 2008 Apr 15;586(8):2093-106. doi: 10.1113/jphysiol.2007.150540. Epub 2008 Feb 14.
Kv4 channels mediate most of the somatodendritic subthreshold operating A-type current (I(SA)) in neurons. This current plays essential roles in the regulation of spike timing, repetitive firing, dendritic integration and plasticity. Neuronal Kv4 channels are thought to be ternary complexes of Kv4 pore-forming subunits and two types of accessory proteins, Kv channel interacting proteins (KChIPs) and the dipeptidyl-peptidase-like proteins (DPPLs) DPPX (DPP6) and DPP10. In heterologous cells, ternary Kv4 channels exhibit inactivation that slows down with increasing depolarization. Here, we compared the voltage dependence of the inactivation rate of channels expressed in heterologous mammalian cells by Kv4.2 proteins with that of channels containing Kv4.2 and KChIP1, Kv4.2 and DPPX-S, or Kv4.2, KChIP1 and DPPX-S, and found that the relation between inactivation rate and membrane potential is distinct for these four conditions. Moreover, recordings from native neurons showed that the inactivation kinetics of the I(SA) in cerebellar granule neurons has voltage dependence that is remarkably similar to that of ternary Kv4 channels containing KChIP1 and DPPX-S proteins in heterologous cells. The fact that this complex and unique behaviour (among A-type K(+) currents) is observed in both the native current and the current expressed in heterologous cells by the ternary complex containing Kv4, DPPX and KChIP proteins supports the hypothesis that somatically recorded native Kv4 channels in neurons include both types of accessory protein. Furthermore, quantitative global kinetic modelling showed that preferential closed-state inactivation and a weakly voltage-dependent opening step can explain the slowing of the inactivation rate with increasing depolarization. Therefore, it is likely that preferential closed-state inactivation is the physiological mechanism that regulates the activity of both ternary Kv4 channel complexes and native I(SA)-mediating channels.
Kv4通道介导神经元中大部分树突-胞体阈下运作的A型电流（I(SA)）。该电流在调节动作电位时间、重复放电、树突整合和可塑性方面发挥着重要作用。神经元Kv4通道被认为是由Kv4孔形成亚基与两种辅助蛋白组成的三元复合物，这两种辅助蛋白分别是Kv通道相互作用蛋白（KChIPs）以及二肽基肽酶样蛋白（DPPLs）中的DPPX（DPP6）和DPP10。在异源细胞中，三元Kv4通道表现出失活现象，且随着去极化程度的增加，失活速度减慢。在此，我们比较了由Kv4.2蛋白在异源哺乳动物细胞中表达的通道与包含Kv4.2和KChIP1、Kv4.2和DPPX-S或Kv4.2、KChIP1和DPPX-S的通道失活速率的电压依赖性，发现这四种情况下失活速率与膜电位之间的关系各不相同。此外，来自天然神经元的记录表明，小脑颗粒神经元中I(SA)的失活动力学具有的电压依赖性与异源细胞中包含KChIP1和DPPX-S蛋白的三元Kv4通道极为相似。在天然电流以及由包含Kv4、DPPX和KChIP蛋白的三元复合物在异源细胞中表达的电流中均观察到这种复杂且独特的行为（在A型钾电流中），这一事实支持了以下假说：在神经元中通过体细胞记录的天然Kv4通道包含这两种辅助蛋白。此外，定量全局动力学建模表明优先的关闭状态失活以及一个弱电压依赖性的开放步骤可以解释随着去极化增加失活速率减慢的现象。因此，优先的关闭状态失活很可能是调节三元Kv4通道复合物和天然I(SA)介导通道活性的生理机制。
