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Thermodynamics and Energetics of voltage-gated ion channels

电压门控离子通道的热力学和能量学

基本信息

批准号：
10226481
负责人：
Baron Chanda
金额：
$ 21.94万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226481
关键词：
Thermodynamics Energetics voltage gated ion

项目摘要

Ion channels are the primary sensors of many physical stimuli such as voltage, lateral stretch, osmolality and temperature. Of these, the fundamental biophysical principles of temperature-sensing and temperature- dependent gating are perhaps the most enigmatic. Despite the fact that many ion channels in the voltage- gated ion channel (VGIC) superfamily are involved in temperature sensing and that many high-resolution structures are now available, a common structural motif or module responsible for this temperature- dependence has not yet been identified. One possibility is that temperature-sensing phenotype is due to convergent evolution and different ion channels have become temperature-sensitive in different ways. According to this line of thinking, unlike a chemical signal, temperature gating may have less to do with a specific structural fold since it is not bound by rules of stereochemistry. The goal of this proposal is to broadly explore the mechanisms of temperature-dependent gating in ion channels using a multi-pronged approach. In specific aim 1, we will apply the newly developed thermodynamic tools and multi-dimensional NMR spectroscopy to thoroughly characterize the biophysical mechanisms that underlie enhanced temperature- sensitive gating in engineered ion channels. We will test the hypothesis that state-dependent change in solvation of side-chains and lipid acyl chains may underlie temperature-dependence in these ion channels. In the specific aim 2, we will explore the temperature-dependence of electromechanical coupling. The goal here is to use rational design approach to test an alternate mechanism of temperature sensing. In this paradigm, the temperature-sensitivity is not due to the sensor itself but due to temperature-dependence of coupling interactions between the voltage-sensor and pore gates. In specific aim 3, we will probe the mechanisms of temperature-dependent gating in a biochemically tractable prokaryotic channel. We have recently identified that the calcium-dependent gating of MthK potassium ion channel is highly temperature-sensitive. Our proposed studies will combine calorimetry, electrophysiology and structural biology with the power of reverse genetics to understand the molecular mechanisms that underlie temperature-dependence in these archeal ion channels. Taken together, the three specific aims will broadly study the mechanisms of temperature-dependent gating in channels of the VGIC superfamily. We expect that this multi-disciplinary approach will shed light on the biophysical mechanisms that underlie exquisite temperature-dependence in many ion channels.

离子通道是许多物理刺激的主要传感器，如电压、横向拉伸、渗透压