Voltage-gated sodium channels in lysosomal physiology

溶酶体生理学中的电压门控钠通道

基本信息

  • 批准号:
    10449969
  • 负责人:
  • 金额:
    $ 49.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-15 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

The biophysical properties and the regulation of plasma membranes have been extensively studied for several decades. Hundreds of ion channels have been discovered. They regulate essentially every aspect of cell biology and physiological functions, ranging from muscle contraction and neuronal signaling to hormone secretion and gene expression. In contrast, the biophysical properties of intracellular organelle membranes have been much less investigated. In this propose, we extend our preliminary studies of lysosomal membranes, with focus on lysosomal sodium channels. Lysosomes are the digestion and recycling center in mammalian cells. They play central roles in cellular clearance, nutrient recycling, energy generation and signaling. Dysfunction of lysosomes leads to severe diseases such as lysosomal storage diseases and neurodegenerative diseases including Parkinson’s and Alzheimer’s. Recent electrophysiological recordings, molecular cloning, protein chemistry and mouse genetics studies have started to define the properties of lysosomal membranes. Whole-lysosome current-clamp recording has discovered that a subset of lysosomes generate action potential-like membrane depolarization spikes. The ability to generate spikes is critically dependent on a novel voltage-gated sodium-permeable channel formed by the two-pore repeat channel 1 (TPC1) protein. In addition, preliminary studies suggest that TPC channels are coupled to the metabolic state and nutrient availability of the cell, and to the luminal pH of the organelle. We propose three specific aims to expand our studies. Patch clamp recordings will be used to test the hypothesis that lysosomal excitability is widely expressed and can be found in both excitable and non-excitable cells. Whether the excitability is regulated by metabolic state and the availability of nutrients will also be tested (Aim 1). TPC channels are controlled by cytosolic ATP concentration via the mTOR kinase. We will use biochemical approaches to define the mechanisms underlying the channel’s ATP sensitivity (Aim 2). TPC channels are generally selective for sodium, and evidences suggest that the channels are also calcium-permeable. In Aim 3, biochemical and electrophysiological experiments will be performed to define the channel permeation and its regulation by calcium (Aim 3). Given the physiological importance of lysosomes, the proposed studies will help fill the knowledge gap in our understanding of the properties of lysosomal membranes and their functions under normal and pathological states such as neurodegenerative diseases.
质膜的生物物理特性及其调控已被广泛研究

项目成果

期刊论文数量(0)
专著数量(0)
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专利数量(0)

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Dejian Ren其他文献

Dejian Ren的其他文献

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{{ truncateString('Dejian Ren', 18)}}的其他基金

Regulation of lysosomal potassium channels
溶酶体钾通道的调节
  • 批准号:
    9763115
  • 财政年份:
    2019
  • 资助金额:
    $ 49.08万
  • 项目类别:
Voltage-gated sodium channels in lysosomal physiology
溶酶体生理学中的电压门控钠通道
  • 批准号:
    9912823
  • 财政年份:
    2019
  • 资助金额:
    $ 49.08万
  • 项目类别:
Voltage-gated sodium channels in lysosomal physiology
溶酶体生理学中的电压门控钠通道
  • 批准号:
    9753478
  • 财政年份:
    2019
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of lysosomal potassium channels
溶酶体钾通道的调节
  • 批准号:
    10428466
  • 财政年份:
    2019
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of lysosomal potassium channels
溶酶体钾通道的调节
  • 批准号:
    9901594
  • 财政年份:
    2019
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of Neuronal Excitability by Extracellular Calcium
细胞外钙对神经元兴奋性的调节
  • 批准号:
    8217080
  • 财政年份:
    2011
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of Neuronal Excitability by Extracellular Calcium
细胞外钙对神经元兴奋性的调节
  • 批准号:
    8604432
  • 财政年份:
    2011
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of Neuronal Excitability by Extracellular Calcium
细胞外钙对神经元兴奋性的调节
  • 批准号:
    8791347
  • 财政年份:
    2011
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of Neuronal Excitability by Extracellular Calcium
细胞外钙对神经元兴奋性的调节
  • 批准号:
    8410035
  • 财政年份:
    2011
  • 资助金额:
    $ 49.08万
  • 项目类别:
Regulation of Neuronal Excitability by Extracellular Calcium
细胞外钙对神经元兴奋性的调节
  • 批准号:
    8083357
  • 财政年份:
    2011
  • 资助金额:
    $ 49.08万
  • 项目类别:

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