Synaptic function of BK channel-interacting proteins

BK 通道相互作用蛋白的突触功能

• 批准号: 8964358
• 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
• 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/8964358
• 关键词: ARA9 protein; Alzheimer' s Disease; Anatomy; Ataxia; Behavior; Biological Assay; Brain; Caenorhabditis elegans; Calcium; Calcium Channel; Chemotaxis; Complex; Disease; Docking; Dorsal; Electron Microscopy; Endoplasmic Reticulum; Epilepsy; Exocytosis; Fluorescence; Frequencies; Genetic Screening; Goals; Hippocampus (Brain); Homologous Gene; Knowledge; Label; Learning; 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; Rattus; Regulation; Role; Ryanodine Receptors; Shapes; Site; Solutions; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Testing; Training; Xenopus oocyte; base; cholinergic; conditioning; density; gain of function; genetic regulatory protein; human disease; 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; public health relevance; relating to nervous system; response; sensor; synaptic function; vesicle-associated membrane protein; voltage

 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（由申请人提供）：突触前神经末梢是一个包含许多控制神经递质释放的蛋白质的复杂结构，识别各种调节蛋白并阐明其作用机制对于理解突触前神经末梢如何快速、动态地调节神经递质释放至关重要。通道是一种高电导电压/钙门控钾通道，与突触前末端的电压门控钙通道共定位并服务作为神经递质释放的强大负调节因子。为了鉴定神经递质释放的新型调节因子，我们进行了遗传筛选，以分离出抑制 bkip-2 和 bkip-4 突变体中由过度活跃的 BK 通道引起的昏睡表型的突变体。初步研究表明，BKIP-2 和 BKIP-4 均具有哺乳动物同源物，但其功能未知。 BKIP-2 是神经元中 BK 通道功能所必需的，而 BKIP-4 通过似乎独立于 BK 通道的机制调节神经递质释放。该提案的具体目的是：（1）检验 BKIP-4 的假设。通过控制突触前 Ca2+ 浓度来调节神经递质释放；(2) 确定 BKIP-4 突变是否改变神经解剖结构，以及 BKIP-4 功能在哺乳动物中是否保守； BKIP-2 如何调节突触前 BK 通道的功能 长期目标是回答各种突触前蛋白如何相互作用以动态塑造神经回路以及为什么这些蛋白的突变可能导致多种人类疾病的重要问题。