Gating of Neuronal Kv4 Channels

神经元 Kv4 通道的门控

基本信息

批准号：
7862618
负责人：
MANUEL L COVARRUBIAS
金额：
$ 38.63万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862618
关键词：
Applications Grants Arts Attention Autistic Disorder Biochemical Brain Calcium-Binding Proteins Charge Communication Complex Computer Simulation Computing Methodologies Coupled Cysteine Dipeptidyl Peptidases Disease Disulfides Drosophila genus Electrostatics Epilepsy Funding Goals Heart Hippocampus (Brain)Immobilization In Vitro Interdisciplinary Study Kinetics Kv channel-interacting protein 1 Kv4 channel Laboratories Light Link Location Mammalian Cell Membrane Membrane Potentials Methodology Methods Molecular Molecular Conformation Mutation N-terminal National Institute of Neurological Disorders and Stroke Neurologic Neurons Nitric Oxide Pain Potassium Potassium Channel Property Protein Biochemistry Protein Isoforms Proteins Regulation Rest Signal Transduction Site Site-Directed Mutagenesis Solutions System Tail Technology Testing Time Translations Work Xenopus oocyte analytical tool base crosslink experience insight interdisciplinary approach interfacial molecular dynamics novel patch clamp research study sensor software development voltage

项目摘要

The long~term goal of this project is to shed light on t molecular mechanisms that govern the function and regulation of the neuronal somatodendritic A~type assium current (I$A), Typically, ISA operates in the subthreshold range of membrane potentials and is a pivotal player in the ensemble of active membrane currents that regulate somatodendrilic signal integrati9n; therefore, it has a broad impact on the electrical plasticity of the brain. The Kv4 channel complex is th~ l moleculpr correlate of ISA. This complex includes the KV4 pore-forming a.~subunit encompassing three modulrr domains common to all voltage-gated K" channets: tetramerization (T1) domain, voltage-sensing domain a~ pore domain. In addition, Kv4 ((~subunits associate with at least two specific classes of auxiliary p~subunits ChiPs and DPPs). Although ground breaking S1udies of the OfO$ophila Shaker~B and bacterial potassium annels have helped explain fundamental properties (ionic selectivity, voltage-dependent gating and open-s te inactivation), many problems conceming relevant regulatory mechanisms remain unsolved. Given th cytoplasmic location of the T1 domain, its likely contribution to gating is one of the most intriguing Probl~ms . With NINDS suppon, previous studies from the PI's laboratory strongly support this contribution in Kv channels and its modulation by nitric oxide (NO). However, the molecular mechanisms have remained elu ive. To break new ground, this project will investigate the molecular mechanisms under1ying the contributions of the T1 domain to activation (Aim 1) and inactivation (Aim 2) in the Kv4 channel complex. The proposed actIvity will focus on putative moving parts that surround the interfacial Zn .... site, which is the targ~ of NO mod y l~lon ;. and t~e exp~rimental approach is based ?n a multidiscIplinary research plan that combines electrop~StOloglcal , biochemical, molecular and computational methOdologies. This work is likely to impact the stud of neurological entities possibly linked to the Kv4 channel complex, such as epilepsy, pain plasticity, neur egenerative disorders, and autism.

该项目的长期目标是阐明T分子机制，该机制控制了神经元体体的功能和调节的typy a〜型assium电流（i $ a），通常是ISA在膜电位的亚阈值范围内运行，并且是IS活跃膜电流集合中的一个关键播放器，该集合调节了体内信号Integrati9n；因此，它对大脑的电塑性具有广泛的影响。 KV4通道复合物是ISA的Th〜l分子相关。该复合物包括所有电压门控k“通道共有的三个ModulRR域的KV4孔形成A。至少有两种特定类别的辅助P〜亚基芯片和DPP）。灭活）鉴于T1域的细胞质位置，许多相关的调节机制仍然没有解决。在KV通道及其通过一氧化氮的调制（NO）。（AIM 2）在KV4通道复合体中。提出的活动将集中于围绕界面Zn的假定运动部件....这是无模式的targ〜。 t〜e实验方法基于一个跨学科研究计划，该计划结合了电动，生化，分子和计算方法。这项工作可能会影响可能与KV4通道复合物有关的神经系统实体的研究，例如癫痫，疼痛可塑性，神经发电性疾病和自闭症。