Sodium Leak Channels and Regulation by Neurotransmitters

钠泄漏通道和神经递质的调节

基本信息

批准号：
7753155
负责人：
Dejian Ren
金额：
$ 32.48万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753155
关键词：
Animals Birth Brain region Breathing Caenorhabditis elegans Calcium Calcium Channel Cations Cell membrane Cesium Defect Drosophila genus Embryonic Development Epilepsy Family Family member Gene Expression Genes Hippocampus (Brain)Hour In Situ Hybridization Ion Channel Ion Channel Protein Ions Knock-out Mammals Membrane Potentials Molecular Mus Muscarine Mutagenesis Mutant Strains Mice Names Nervous system structure Neurons Neuropeptide Receptor Neuropeptides Neurotensin Neurotransmitters Nomenclature Northern Blotting Paralysed Physiological Potassium Channel Proteins Receptor Activation Regulation Relative (related person)Rest Role Seizures Sodium Sodium Channel Spinal Cord Substance P System TACR1 gene Testing base extracellular hippocampal pyramidal neuron member mutant neuronal excitability novel patch clamp protein function pup receptor response voltage

Animals Birth Brain region Breathing Caenorhabditis elegans Calcium Calcium Channel Cations Cell membrane Cesium Defect Drosophila genus Embryonic Development Epilepsy Family Family member Gene Expression Genes Hippocampus (Brain)Hour In Situ Hybridization Ion Channel Ion Channel Protein Ions Knock-out Mammals Membrane Potentials Molecular Mus Muscarine Mutagenesis Mutant Strains Mice Names Nervous system structure Neurons Neuropeptide Receptor Neuropeptides Neurotensin Neurotransmitters Nomenclature Northern Blotting Paralysed Physiological Potassium Channel Proteins Receptor Activation Regulation Relative (related person)Rest Role Seizures Sodium Sodium Channel Spinal Cord Substance P System TACR1 gene Testing base extracellular hippocampal pyramidal neuron member mutant neuronal excitability novel patch clamp protein function pup receptor response voltage

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项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on a sodium leak channel (NALCN) and its regulation by neurotransmitters in the nervous systems. NALCN ion channel belongs to the family that also includes the ten voltage-gated calcium channels and ten sodium channels. However, the NALCN channel is non-selective (permeable to sodium, calcium and potassium), and the channel's activation is voltage-independent. In the mutant mice deficient in the channel gene, there is defect in breathing rhythm and the mutant animals do not survive beyond 24 hours of birth. Thus, NALCN is one of the few ion channels indispensable for animal's survival. The mutant hippocampal neurons lack the cesium and TTX-insensitive sodium leak current and the neurons' membrane potential is little sensitive to changes in extracellular sodium concentrations. Using Northern blot and in situ hybridization, aim 1 will localize the gene expression in the animal. Aim 2 will determine the molecular mechanisms underlying NALCN's unique ion selectivity. Aim 3 will use patch clamp to compare the excitabilities of the wild-type and the mutant neurons and determine the contribution of NALCN channel to neuronal excitability. Aim 4 will examine how the NALCN channel is regulated by neurotransmitters. Results from these studies will reveal the physiological roles of this vital gene. They may also reveal how the function of the protein can influence neuronal excitabilities in physiological and pathophysiological conditions such as paralysis, seizure and epilepsy.

描述（由申请人提供）：该提案重点介绍钠泄漏通道（NALCN）及其在神经系统中对神经递质的调节。 Nalcn离子通道属于该家族，其中还包括十个电压门控钙通道和十个钠通道。但是，NALCN通道是非选择性的（可渗透到钠，钙和钾），并且该通道的激活是不依赖电压的。在缺乏通道基因的突变小鼠中，呼吸节奏缺陷，突变动物无法生存超过24小时的出生。因此，NALCN是动物生存必不可少的几个离子通道之一。突变的海马神经元缺乏宫颈和TTX不敏感的钠泄漏电流，而神经元的膜电位对细胞外钠浓度的变化几乎没有敏感。使用北印迹和原位杂交，AIM 1将在动物中定位基因表达。 AIM 2将确定NALCN独特离子选择性的分子机制。 AIM 3将使用斑块夹比较野生型和突变神经元的兴奋性，并确定NALCN通道对神经元兴奋性的贡献。 AIM 4将检查NALCN通道如何受神经递质调节。这些研究的结果将揭示该重要基因的生理作用。它们还可以揭示蛋白质的功能如何影响生理和病理生理状况（例如瘫痪，癫痫发作和癫痫）中的神经元兴奋性。