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

海马的典型瞬时受体电位 (TRPC) 亚家族功能。

• 批准号: 8394934
• 负责人: DAVID E. CLAPHAM
• 金额: $ 41.34万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394934
• 关键词: Acute; Address; Affect; Agonist; Alzheimer' s Disease; Amnesia; Amygdaloid structure; Antibody Specificity; Behavioral; Birth; Brain; Brain region; Breeding; Calcium; Cell membrane; Cells; Characteristics; Chemosensitization; Cholecystokinin B Receptor; Coupled; Development; Disease; Encephalitis; Exhibits; Family; Fright; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Glutamates; Health; Hippocampus (Brain); Human; Ion Channel; Knock-out; Knockout Mice; Learning; Link; Mammalian Cell; Mammals; Medial; Mediating; Membrane; Memory; Memory impairment; Messenger RNA; Metabotropic Glutamate Receptors; Mus; Muscarinic Acetylcholine Receptor; Mutant Strains Mice; Neuraxis; Neurons; Neurotransmitter Receptor; Operative Surgical Procedures; Oxygen; Phosphatidylinositol 4,5-Diphosphate; Phospholipase C; Property; Protein Array; Proteins; Pseudogenes; Receptor Activation; Receptor Protein-Tyrosine Kinases; Role; Slice; Starvation; Surface; Synapses; TRP channel; TRPC1 protein; Temporal Lobe Epilepsy; Testing; Work; cancer surgery; design; improved; long term memory; member; neurotransmitter release; new therapeutic target; protein function; receptor; research study; response; synaptic function; tumor; voltage; way finding

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.

描述(申请人提供)：离子通道亚单位的典型瞬时受体潜力家族由7个不同的基因产物(TRPC1-7)组成，其中大部分在中枢神经系统中表达。这一类的三个亚家族成员(TRPC1、TRPC4和TRPC5)在海马区高表达。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，磷脂酶C通过G蛋白偶联受体亚型和酪氨酸激酶受体亚型激活或增强由这些蛋白介导的电流。特别是，与GQ/11相关的受体，如1型代谢性谷氨酸和M1、M3和M5受体，通过改变质膜PIP2和增加细胞内钙离子浓度来激活这些电流。TRPC1/4/5亚家族在海马区的功能尚不清楚。我们假设，海马体功能是由激活或增强这些兴奋性离子通道的受体调节的。我们已经培育出缺乏TRPC4、TRPC5、TRPC4和TRPC5基因的小鼠，获得了TRPC1基因敲除小鼠，并正在培育TRPC1/4/5三重敲除小鼠。在这里，我们建议使用这些小鼠通过蛋白质定位、行为学研究、海马区急性脑片记录和分离的海马神经元记录来了解这些离子通道在海马区的功能。这些研究的结果应该阐明受体介导的海马体介导的空间和上下文记忆的改变，并确定影响海马体的疾病和手术的新的治疗靶点。