Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan.
Neuron. 2012 Dec 6;76(5):945-61. doi: 10.1016/j.neuron.2012.10.012.
KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABA(A) receptor (GABA(A)R)-mediated synaptic transmission. We also identified reduced cell surface expression of GABA(A)R in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABA(A)R-associated protein (GABARAP) that is known to be involved in GABA(A)R trafficking. KIF5A regulated neuronal surface expression of GABA(A)Rs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.
KIF5（也称为驱动蛋白-1）家族成员，包括 KIF5A、KIF5B 和 KIF5C，是微管依赖性的分子马达，对神经元功能很重要。在 KIF5 中，KIF5A 是神经元特异性的，在中枢神经系统中高度表达。然而，KIF5A 的具体作用仍不清楚。在这里，我们建立了条件性 Kif5a 敲除小鼠，其中 KIF5A 蛋白表达在神经元中被出生后抑制。由于 GABA(A) 受体 (GABA(A)R)-介导的突触传递受损，导致电描记图异常，从而观察到癫痫表型。我们还发现，在敲除神经元中 GABA(A)R 的细胞表面表达减少。重要的是，我们确定 KIF5A 与 GABA(A)R 相关蛋白（GABARAP）特异性相互作用，已知 GABARAP 参与 GABA(A)R 的运输。KIF5A 通过与 GABARAP 的相互作用调节 GABA(A)R 的神经元表面表达。这些结果提供了对 KIF5A 调节抑制性神经传递的分子机制的深入了解。
