Regulation of lysosomal potassium channels

溶酶体钾通道的调节

基本信息

批准号：
10428466
负责人：
Dejian Ren
金额：
$ 32.58万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10428466
关键词：
3-Dimensional Alzheimer&apos s Disease Autophagocytosis Autophagosome Bathing Biophysics Calcium Cations Cell membrane Cell physiology Chloride Ion Closure by clamp Complex Cytosol Digestion Disease Exocytosis FRAP1 gene Face Functional disorder Genetic Variation Goals Growth Factor Heterogeneity Hormone secretion Human Insulin Ion Channel Ions Kinetics Knockout Mice Link Lumen of the Lysosome Lysosomal Storage Diseases Lysosomes Malignant Neoplasms Measures Mediating Membrane Membrane Potentials Modeling Molecular Molecular Genetics Muscle Contraction Nerve Degeneration Neurodegenerative Disorders Neurons Organelles Parkinson Disease Pathologic Permeability Phosphotransferases Physiological Physiology Play Potassium Potassium Channel Predisposition Principal Investigator Property Protein Chemistry Protein Kinase Proteins Proto-Oncogene Proteins c-akt Proton Pump Recycling Regulation Research Role Serum Shapes Signal Transduction System Testing Time Tissues VDAC1 gene Vesicle base experimental study genome wide association study genome-wide knockout animal mouse model novel patch clamp potassium ion programs recruit repaired small molecule vacuolar H+-ATPase voltage

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Ren, Dejian The overall goal of the proposed research is to understand the function and the regulation of potassium ion channels to the function of lysosomes. Potassium is the most abundant intracellular ion that faces both plasma membrane and organelle membrane. Plasma membranes are highly permeable to potassium. More than 80 potassium channels have now been discovered to mediate such plasma membrane potassium permeability. In contrast, how potassium passes intracellular organelles such as lysosomes is much less understood. Lysosomes play fundamental roles in cellular clearance, digestion, recycling, exocytosis and membrane repair. Because of high concentration of calcium in the lumen, lysosomes are also calcium stores from which calcium is released into cytosol to shape cytosolic calcium kinetics and to regulate muscle contraction and hormone secretion. Lysosomal dysfunction has been linked to pathophysiological conditions such as lysosomal storage diseases, cancer and neurodegeneration. Therefore understanding how lysosomal membrane mediates ionic permeability is important to our understanding of the organelle’s physiology function. We recently discovered a novel protein TMEM175 that forms a potassium-selective channel in lysosomal membrane. Genetic variation in human TMEM175 is also implicated in Parkinson’s disease. We propose three specific aims to expand our preliminary findings. In Aim 1, we will use patch clamp recordings to compare wild-type and TMEM175 knockout animals and will test whether there are other major lysosomal potassium channels in addition to TMEM175. Unlike those of plasma membrane channels, the functions of lysosomal potassium channels are largely unknown. In Aim 2, we will use the TMEM175 knockout mouse model to test the hypothesis that potassium channels regulate the normal working of lysosomes including organelle membrane potential regulation, luminal acidification, vesicle fusion and autophagy. In Aim 3, we will test whether TMEM175, like many other potassium channels on plasma membrane, is regulated by protein kinases. Using protein chemistry experiments, we will also determine the structural requirements for such regulation. Because of the fundamental function of lysosomes, the studies will reveal how lysosomal potassium channels contribute to the organelle’s function under physiological and pathological conditions. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page

项目主任/首席研究员（后、一、中）：任德建该研究的总体目标是了解钾离子的功能和调节钾是面向血浆的最丰富的细胞内离子。细胞膜和细胞器膜对钾的渗透性超过 80。现在已经发现钾通道可以介导这种质膜钾渗透性。相比之下，人们对钾如何通过溶酶体等细胞内细胞器的了解要少得多。溶酶体在细胞清除、消化、回收、胞吐作用和膜修复中发挥重要作用。由于管腔内钙浓度高，溶酶体也是钙储存库，钙可从溶酶体中储存。被释放到细胞质中以塑造细胞质钙动力学并调节肌肉收缩和激素溶酶体功能障碍与溶酶体储存等病理生理状况有关。因此了解溶酶体膜如何介导离子。渗透性对于我们理解细胞器的生理功能很重要，我们最近发现了一个。在溶酶体膜中形成钾选择性通道的新型蛋白质 TMEM175 遗传变异。人类中的 TMEM175 也与帕金森病有关，我们提出了三个具体目标来扩大我们的研究范围。在目标 1 中，我们将使用膜片钳记录来比较野生型和 TMEM175。淘汰动物并将测试除了敲除之外是否还有其他主要的溶酶体钾通道 TMEM175 与质膜通道不同，溶酶体钾通道的功能是在目标 2 中，我们将使用 TMEM175 敲除小鼠模型来检验以下假设：钾通道调节溶酶体的正常工作，包括细胞器膜电位调节、管腔酸化、囊泡融合和自噬在目标 3 中，我们将测试 TMEM175 是否类似。质膜上的许多其他钾通道均由蛋白激酶调节。化学实验中，我们还将确定这种调节的结构要求。溶酶体的基本功能，研究将揭示溶酶体钾通道如何促进细胞器在生理和病理条件下的功能。 OMB 编号 0925-0001/0002（修订版 01/18 批准至 03/31/2020）页码

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins.

SARS-CoV-2 辅助蛋白 Orf3a 不是离子通道，但确实与运输蛋白相互作用。

DOI：
10.7554/elife.84477
发表时间：
2023-01-25
期刊：
eLife
影响因子：
7.7
作者：
Miller AN;Houlihan PR;Matamala E;Cabezas-Bratesco D;Lee GY;Cristofori-Armstrong B;Dilan TL;Sanchez-Martinez S;Matthies D;Yan R;Yu Z;Ren D;Brauchi SE;Clapham DE
通讯作者：
Clapham DE

Lysosomal channels sensing forces.

溶酶体通道感知力。