Regulation of kainate-type glutamate receptors by auxiliary subunits

 描述（由申请人提供）：离子型谷氨酸受体负责哺乳动物大脑中的快速兴奋性神经传递。有三种类型的离子型谷氨酸受体，命名为AMPA，NMDA和红藻氨酸受体。红藻氨酸盐型谷氨酸受体存在于突触前和突触后位置，在那里它们调节神经递质释放并增加神经元兴奋性。红藻氨酸受体的失调与多种神经系统疾病有关。特别是，这些受体的异常表达模式可能有助于颞叶癫痫的海马过度兴奋。红藻氨酸受体是四聚体结构，由五个不同的孔形成亚基（GluK 1-GluK 5）的组合组成。此外，红藻氨酸受体可以通过与辅助亚基Neto 1和Neto 2共组装来调节。孔形成亚基和辅助亚基在整个大脑中显示出不同的表达模式，并且可以在整个发育过程中以及响应于病理条件而受到调节。这项工作的目标是确定孔形成和辅助亚基之间的亚基特异性相互作用的功能影响，以预测神经元受体的特征。此外，本发明还提供了一种方法， 我们将使用嵌合亚基和定点诱变来确定Neto 1和Neto 2亚基之间的结构差异，这些结构差异引起它们不同的功能效应。这项工作的结果将阐明辅助亚基在兴奋性神经传递调节中的作用，并将提出通过靶向调节特定受体群体治疗神经系统疾病的新方法。

 DESCRIPTION (provided by applicant): The ionotropic glutamate receptors are responsible for fast excitatory neurotransmission in the mammalian brain. There are three types of ionotropic glutamate receptors, named the AMPA, NMDA and kainate receptors. Kainate-type glutamate receptors are found in both pre- and post-synaptic locations, where they regulate neurotransmitter release and increase neuronal excitability. Dysregulation of kainate receptors has been linked to a variety of neurological disorders. In particular, abnormal expression patterns of these receptors may contribute to hyperexcitability of the hippocampus in temporal lobe epilepsy. The kainate receptors are tetrameric in structure, composed from a combination of five different pore-forming subunits (GluK1-GluK5). In addition, the kainate receptors can be regulated by co-assembly with the auxiliary subunits Neto1 and Neto2. Both the pore-forming and auxiliary subunits show distinct patterns of expression throughout the brain and may be regulated throughout development and in response to pathological conditions. The goal of this work is to determine the functional impact of subunit-specific interactions between pore-forming and auxiliary subunits, in order to predict the characteristics of neuronal receptors. In addition, we will use chimeric subunits and site-directed mutagenesis to determine the structural differences between the Neto1 and Neto2 subunits that give rise to their distinct functional effects. The results of this work will illuminate the roles that auxiliary subunits play in the regulation of excitatory neurotransmission and will suggest novel approaches for the treatment of neurological disorders through the targeted regulation of specific receptor populations.