Canonical Transient Receptor Potential (TRPC) subfamily function in Hippocampus.

描述（由申请人提供）：典型瞬时受体电位离子通道亚基家族包括7个不同的基因产物（TRPC1-7），其中大部分在中枢神经系统中表达。这类的三个亚家族成员（TRPC1、TRPC4和TRPC5）在海马中高度表达。这些离子通道亚基形成具有不同特征的同质和异质通道。此外，这些蛋白介导的电流通过G蛋白偶联受体和酪氨酸激酶受体的亚型被磷脂酶C激活或增强。特别是，Gq/11连接受体，如1型代谢性谷氨酸和M1、M3和M5毒蕈碱受体，通过改变质膜PIP2和增加细胞内Ca2+浓度来激活这些电流。TRPC1/4/5亚家族在海马中的功能尚不清楚。我们假设海马功能是由激活或增强这些兴奋性离子通道的受体调节的。我们培育了缺乏TRPC4、TRPC5、TRPC4和TRPC5基因的小鼠，获得了TRPC1敲除小鼠，并正在培育TRPC1/4/5三敲除小鼠。在这里，我们建议使用这些小鼠，通过蛋白质定位、行为研究、海马的急性脑切片记录和分离海马神经元的记录来了解海马中这些离子通道的功能。这些研究的结果将阐明受体介导的海马介导的空间和情境记忆的改变，并为影响海马的疾病和手术确定新的治疗靶点。

DESCRIPTION (provided by applicant): The Canonical Transient Receptor Potential family of ion channel subunits comprise 7 distinct gene products (TRPC1-7), most of which are expressed in the central nervous system. Three subfamily members of this class (TRPC1, TRPC4, and TRPC5) are highly expressed in the hippocampus. These ion channel subunits forms homomeric and heteromeric channels with distinct characteristics. In addition, the currents mediated by these proteins are activated or potentiated by phospholipase C via subtypes of G protein-coupled receptors and tyrosine kinase receptors. In particular, Gq/11-linked receptors such as the type 1 metabotropic glutamate and M1, M3, and M5 muscarinic receptors, activate these currents by altering plasma membrane PIP2 and increasing intracellular Ca2+ concentrations. The function of the TRPC1/4/5 subfamily in hippocampus is not known. We hypothesize that hippocampal function is modulated by receptors that activate or potentiate these excitatory ion channels. We have generated mice lacking the TRPC4, TRPC5, both TRPC4 and TRPC5 genes, obtained the TRPC1 knockout mouse, and are breeding TRPC1/4/5 triple knockout mice. Here we propose to use these mice to understand the function of these ion channels in the hippocampus using protein localization, behavioral studies, acute brain slice recordings of hippocampus, and recordings of isolated hippocampal neurons. The results of these studies should clarify receptor-mediated alteration of hippocampal-mediated spatial and contextual memory, and identify new therapeutic targets for diseases and surgeries that affect the hippocampus.