AMPA受体亚型GluA4单通道电流动力学特性的研究

AMPA receptors are widely expressed in Central Nervous System (CNS). They open and close quickly, and thereby mediate fast excitatory synaptic transmission, which are consequently involved in regulation of learning, memory, synaptic plasticity and other physiological functions. AMPA receptors also mediate excitotoxicity which is closely related to CNS diseases such as Alzheimer's, epilepsy, schizophrenia and other neurodegenerative diseases. Therefore, a better understanding of AMPA receptor gating mechanism is helpful to know how information is processed and encoded in neural network. Here, by combining electrophysiology and molecular biology techniques, we will analyze and compare the single-channel currents of AMPA receptors with mutations. Our study will provide valuable clues to further define glutamate receptor gating mechanism.

AMPA受体广泛分布于中枢神经系统，具有快速激活和失活的特性，是介导快速兴奋性突触传递的重要物质基础；并参与学习、记忆和突触可塑性等生理功能的调节。另外，AMPA受体尚可介导兴奋性神经毒性反应，该毒性反应与阿尔茨海默病、癫痫、精神分裂症以及多种神经退行性疾病有关。因此，阐明AMPA受体的门控机制，对于理解信号如何在神经网络中传递具有重要意义。本课题拟通过分析野生型AMPA受体、三种突变型AMPA受体的单通道电生理学特性，揭示AMPA受体激活和失活的门控机制。

AMPA受体是中枢神经系统重要的兴奋性神经递质，具有快速激活和失活的特性，是介导快速兴奋性突触传递的重要物质基础。X晶体衍射技术表明AMPA受体的脱敏依赖于配体二聚体之间的相互作用，我们的研究表明AMPA受体的脱敏与二聚体间相互作用的稳定性相关，二聚体间相互作用稳定可以减弱脱敏。并且AMPA受体的脱敏除了依赖于二聚体间相互作用外，还依赖于配体-受体口袋的稳定性。另外我们还发现AMPA受体的辅助亚单位蛋白能够增加AMPA受体高频开放模式的开放概率。此研究对揭示AMPA受体激活和失活的门控机制具有重要意义，同时为设计针对AMPA受体的药物提供新的思路。