Synaptic function of BK channel-interacting proteins

BK 通道相互作用蛋白的突触功能

基本信息

批准号：
9266503
负责人：
ZHAO-WEN WANG
金额：
$ 39.88万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266503
关键词：
ARA9 protein Alzheimer&apos s Disease Anatomy Ataxia Behavior Biological Assay Brain Caenorhabditis elegans Calcium Calcium Channel Chemotaxis Complement Complex Disease Docking Dorsal Electron Microscopy Endoplasmic Reticulum Epilepsy Exocytosis Fluorescence Frequencies Genetic Anticipation Genetic Screening Genetic Transcription Goals Hippocampus (Brain)Homologous Gene Hydrocarbons Hyperactive behavior Knowledge Label Learning Lethargies Ligands Mammals Mediating Membrane Memory Memory impairment Molecular Mechanisms of Action Morphology Motor Neurons Mus Mutation Nerve Neurons Neuropeptide Gene Neuropeptide Y Receptor Neuropeptides Phenotype Physiological Play Potassium Channel Presynaptic Terminals Protein Isoforms Proteins RIPK1 gene Rattus Regulation Role Ryanodine Receptors Shapes Site Structure Synapses Synaptic Transmission Synaptic Vesicles System Testing Training Xenopus oocyte base cholinergic conditioning density gain of function genetic regulatory protein human disease immunoreactivity in vivo inhibitor/antagonist knock-down large-conductance calcium-activated potassium channels loss of function mutant nervous system disorder neural circuit neurotransmitter release novel postsynaptic presynaptic presynaptic neurons promoter protein function public health relevance receptor function relating to nervous system response sensor synaptic function vesicle-associated membrane protein voltage

ARA9 protein Alzheimer&apos s Disease Anatomy Ataxia Behavior Biological Assay Brain Caenorhabditis elegans Calcium Calcium Channel Chemotaxis Complement Complex Disease Docking Dorsal Electron Microscopy Endoplasmic Reticulum Epilepsy Exocytosis Fluorescence Frequencies Genetic Anticipation Genetic Screening Genetic Transcription Goals Hippocampus (Brain)Homologous Gene Hydrocarbons Hyperactive behavior Knowledge Label Learning Lethargies Ligands Mammals Mediating Membrane Memory Memory impairment Molecular Mechanisms of Action Morphology Motor Neurons Mus Mutation Nerve Neurons Neuropeptide Gene Neuropeptide Y Receptor Neuropeptides Phenotype Physiological Play Potassium Channel Presynaptic Terminals Protein Isoforms Proteins RIPK1 gene Rattus Regulation Role Ryanodine Receptors Shapes Site Structure Synapses Synaptic Transmission Synaptic Vesicles System Testing Training Xenopus oocyte base cholinergic conditioning density gain of function genetic regulatory protein human disease immunoreactivity in vivo inhibitor/antagonist knock-down large-conductance calcium-activated potassium channels loss of function mutant nervous system disorder neural circuit neurotransmitter release novel postsynaptic presynaptic presynaptic neurons promoter protein function public health relevance receptor function relating to nervous system response sensor synaptic function vesicle-associated membrane protein voltage

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项目摘要

DESCRIPTION (provided by applicant): The presynaptic nerve terminal is a complex structure containing many proteins that control neurotransmitter release. Identifying the various regulatory proteins and elucidating their mechanisms of action are critical to understanding how the presynaptic terminal regulates neurotransmitter release rapidly and dynamically. The BK channel, a high-conductance and voltage/calcium-gated potassium channel, colocalizes with voltage-gated calcium channels at the presynaptic terminal and serves as a powerful negative regulator of neurotransmitter release. To identify novel regulators of neurotransmitter release, a genetic screen was performed to isolate mutants suppressing a lethargic phenotype caused by a hyperactive BK channel in C. elegans. Mutants of bkip-2 and bkip-4 (bkip for BK channel Interacting Protein) were isolated. BKIP-2 and BKIP-4 both have mammalian homologues with unknown functions in the brain. Preliminary studies suggest that BKIP-2 is required for BK channel function in neurons whereas BKIP-4 regulates neurotransmitter release through a mechanism that appears to be independent of the BK channel. The specific aims of this proposal are: (1) test the hypothesis that BKIP-4 regulates neurotransmitter release through controlling presynaptic Ca2+ concentration; (2) determine whether BKIP- 4 mutation alters neural anatomy, and whether BKIP-4 function is conserved in mammals; and (3) determine how BKIP-2 regulates the function of presynaptic BK channels. The long-term goals are to answer the important questions how various presynaptic proteins interact to shape neural circuits dynamically and why mutations of these proteins may cause diverse human diseases.

描述（由适用提供）：突触前神经终端是一个复杂的结构，其中包含许多控制神经递质释放的蛋白质。确定各种调节蛋白并阐明其作用机制对于理解突触前末端如何迅速和动态释放神经递质如何调节。 BK通道是一种高导通和电压/钙门控钾通道，与突触前末端的电压门控钙通道共定位，并用作神经递质释放的强大调节剂。为了鉴定神经递质释放的新型调节剂，进行了一个遗传筛选，以分离抑制秀丽隐杆线虫过度活跃的BK通道引起的昏昏欲息表型的突变体。分离了BKIP-2和BKIP-4（BK通道相互作用蛋白的BKIP）的突变体。 BKIP-2和BKIP-4的哺乳动物同源物在大脑中具有未知功能。初步研究表明，BKIP-2是神经元中BK通道功能所必需的，而BKIP-4通过似乎与BK通道无关的机制调节神经递质释放。该提案的具体目的是：（1）检验以下假设：BKIP-4通过控制突触前Ca2+浓度来调节神经递质的释放；（2）确定BKIP-4突变是否改变了神经解剖结构，以及BKIP-4功能是否在哺乳动物中保守；（3）确定BKIP-2如何调节突触前BK通道的功能。长期目标是回答重要的问题，各种突触前蛋白如何相互作用以动态地塑造神经元电路，以及为什么这些蛋白质的突变会引起人类疾病。