Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Neuron. 2011 Sep 22;71(6):1022-9. doi: 10.1016/j.neuron.2011.08.017. Epub 2011 Sep 21.
KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in nonneuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.
KIBRA 最近被确定为与人类记忆表现相关的基因。尽管已经阐明了 KIBRA 在非神经元细胞中几个不同过程中的作用，但 KIBRA 在神经元中的分子功能尚不清楚。我们发现 KIBRA 可直接与蛋白相互作用的蛋白激酶 1（PICK1）结合，并与 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）形成复合物，后者是大脑中主要的兴奋性神经递质受体。KIBRA 敲低可加速 N-甲基-D-天冬氨酸受体诱导内化后 AMPAR 的回收速率。在小鼠中 KIBRA 的基因缺失会损害海马 CA1 突触的长时程抑制和长时程增强。此外，KIBRA 敲除小鼠在情境恐惧学习和记忆方面存在严重缺陷。这些结果表明，KIBRA 通过调节 AMPAR 转运和突触可塑性来调节大脑的高级功能。
