Dynamic modulation of ionic and lipid signaling by neuronal Kv2 channels

神经元 Kv2 通道对离子和脂质信号传导的动态调节

• 批准号: 9765044
• 负责人: Nicholas C. Vierra
• 金额: $ 6.12万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-09 至 2020-11-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765044
• 关键词: Acute; Address; Anxiety Disorders; Architecture; Biology; Brain; Cell membrane; Cell physiology; Characteristics; Classification; Clinical; Comprehension; Defect; Dendrites; Dense Core Vesicle; Disease; Endoplasmic Reticulum; Enzymes; Epilepsy; Exocytosis; Fellowship; Generations; Goals; Homeostasis; Interneurons; Ion Channel; Knockout Mice; Link; Lipids; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane Lipids; Mentors; Molecular; Mutation; Neuroendocrine Cell; Neurons; Neuropeptides; Organelles; Pathogenesis; Pathogenicity; Physiological; Proteins; Rattus; Regulation; Research; Research Design; Research Personnel; Resources; Role; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Site; Synaptic Vesicles; Techniques; Testing; Tissues; Training; VAPA gene; Voltage-Gated Potassium Channel; autism spectrum disorder; base; hippocampal pyramidal neuron; improved; insight; lipid transport; live cell imaging; nervous system disorder; neuronal cell body; neurophysiology; neurotransmission; novel; novel therapeutic intervention; recruit; spatiotemporal; treatment strategy; uptake; vesicular release; voltage

The training plan outlined in this proposal focuses on defining the fundamental neurophysiological functions controlled by the voltage-gated K+ channel Kv2.1. Kv2.1 channels form prominent plasma membrane (PM) clusters on the neuronal soma that are in close proximity to the endoplasmic reticulum (ER). These Kv2.1- associated ER-PM junctions, or EPJs, often contain Ca2+ handling machinery, including L-type Ca2+ channels (LTCCs) and ryanodine receptor (RyR) ER Ca2+ release channels. In addition to being significant sites of Ca2+ uptake and release, EPJs also serve important roles in modulating cellular lipid handling. Lipid transfer between the ER and PM can be acutely regulated by Ca2+, and lipid-modulating enzymes at EPJs exert a reciprocal effect on cellular Ca2+ dynamics. As Kv2.1 clusters enhance the formation EPJs and may modulate Ca2+ signaling at these sites, Kv2.1 is perfectly poised to integrate and control neuronal Ca2+- and lipid signals. Importantly, clinical findings suggest that Kv2.1-associated EPJs are critical for normal brain function: three distinct mutations in Kv2.1 that disrupt the channel domain required for its clustered organization with EPJs cause severe neurodevelopmental delay. However, the molecular architecture, regulation, and functional roles of Kv2.1- associated EPJs remain poorly understood. This presents a major obstacle to determining how Kv2.1 channels contribute to normal neuronal function and limits our understanding of its contributions to the pathogenesis of debilitating neuronal disorders. Although its role in neurons is not yet clear, Kv2.1 clustering in neuroendocrine cells was found to facilitate the exocytosis of dense-core vesicles (DCV), secretory organelles that in neurons contain diverse neuroactive cargo. As defects in neuronal DCV release are associated with autism, anxiety disorders, and epilepsy, it is important to define the molecular points of intersection between Kv2.1 channels and DCV release. I hypothesize that Kv2.1-associated EPJs control neuronal Ca2+ and lipid signals to regulate DCV release. I will test the central hypothesis by determining the mechanisms by which Kv2.1 channels modulate local Ca2+ and lipid homeostasis and signaling in neurons (Aim 1). These findings will be extended to detailed studies of how Kv2.1 channels contribute to the regulation of somatodendritic DCV release (Aim 2). Successful completion of the proposed research will advance our understanding of the fundamental mechanisms regulating neuron function. Moreover, elucidating the influence of Kv2.1 channels on neuronal DCV release will greatly expand comprehension of the mechanisms underlying DCV exocytosis and may also improve understanding of the mechanisms underlying Kv2.1’s contributions to neurological disorders. Through this fellowship, I will develop 1) a novel understanding of the physiological functions of Kv2.1 channels, and 2) my potential as an independent investigator focused on ion channel biology. These training goals will be facilitated by the detailed research plan, the exceptionally qualified mentors with expertise in the proposed study design, and the outstanding facilities and training resources available at UC Davis.

该提案中的培训计划着重于由电压门控EL KV2.1控制的基本神经生理功能。 ）。 y由Ca2+和脂质调制的酶在kv2 .1群集中对细胞Ca2+动力学产生相互效应脂质信号确定KV2.1通道如何促进神经元功能的主要障碍，并限制了我们对衰弱的神经元疾病的贡献的理解，其在其在神经元中的作用尚未明确促进囊泡（DCV）货物。通过确定KV2.1通道模块化局部CA2+和脂质稳态和神经元中的信号来调节DCV的信号。常规的C DCV释放（AIM 2）。拟议的研究的成功压缩将提高我们对调节神经元功能的基本机制的理解。了解Kv2.1对神经系统疾病的贡献。计划在支撑研究设计以及UC Davis提供的出色设施和培训资源中。