Division of Cardiology, Department of Medicine, Duke University, Medical Center, Durham, NC 27710, USA.
J Biol Chem. 2013 May 10;288(19):13258-68. doi: 10.1074/jbc.M112.434548. Epub 2013 Mar 27.
The necessity for, or redundancy of, distinctive KChIP proteins is not known.
Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons.
KChIP2 is essential for homeostasis in hippocampal neurons.
Mutations in K(A) channel auxiliary subunits may be loci for epilepsy. The somatodendritic IA (A-type) K(+) current underlies neuronal excitability, and loss of IA has been associated with the development of epilepsy. Whether any one of the four auxiliary potassium channel interacting proteins (KChIPs), KChIP1-KChIP4, in specific neuronal populations is critical for IA is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for IA regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V½ for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of IA, hippocampal neurons from Kchip2(-/-) mice showed increased excitability. WT cultured neurons fired only occasional single action potentials, but the average spontaneous firing rate (spikes/s) was almost 10-fold greater in Kchip2(-/-) neurons. In slice preparations, spontaneous firing was detected in CA1 pyramidal neurons from Kchip2(-/-) mice but not from WT. Additionally, when seizures were induced by kindling, the number of stimulations required to evoke an initial class 4 or 5 seizure was decreased, and the average duration of electrographic seizures was longer in Kchip2(-/-) mice compared with WT controls. Together, these data demonstrate that the KChIP2 is essential for physiologic IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.
独特的 KChIP 蛋白的必要性或冗余性尚不清楚。
KChIP2 的缺失导致癫痫易感性增加，以及 IA 减少和海马锥体神经元兴奋性增加。
KChIP2 是海马神经元体内平衡所必需的。
K(A) 通道辅助亚基的突变可能是癫痫的基因位点。位于树突和胞体的 IA（A 型）钾电流是神经元兴奋性的基础，IA 的丧失与癫痫的发生有关。在特定神经元群体中，四个辅助钾通道相互作用蛋白（KChIPs）之一，KChIP1-KChIP4 是否对 IA 至关重要尚不清楚。在这里，我们表明，在海马锥体细胞中大量表达的 KChIP2 对海马神经元中 IA 的调节是必不可少的，并且 Kchip2 的缺失会影响边缘性癫痫的易感性。与 WT 神经元相比，Kchip2 缺失对从分离的海马锥体神经元记录的 IA 的具体影响是幅度减小，以及稳态失活的 V½向超极化电位的偏移。与 IA 的相对丧失一致，来自 Kchip2(-/-) 小鼠的海马神经元表现出更高的兴奋性。WT 培养神经元仅偶尔发出单个动作电位，但 Kchip2(-/-)神经元的平均自发放电率（spikes/s）几乎增加了 10 倍。在切片制备中，来自 Kchip2(-/-) 小鼠的 CA1 锥体神经元中检测到自发放电，但来自 WT 的没有。此外，当通过点燃诱导癫痫发作时，引发初始 4 级或 5 级癫痫发作所需的刺激次数减少，并且与 WT 对照相比，Kchip2(-/-) 小鼠的脑电图癫痫发作持续时间更长。总之，这些数据表明 KChIP2 是生理 IA 调节和体内平衡稳定性所必需的，并且在海马神经元中不同 KChIP 之间没有功能冗余。
