Allostery and voltage sensing of membrane proteins

膜蛋白的变构和电压传感

基本信息

批准号：
8721494
负责人：
Michael Priest
金额：
$ 4.27万
依托单位：
UNIVERSITY OF CHICAGO
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：
2012-09-27 至 2015-09-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721494
关键词：
4-Aminopyridine Affinity Binding Binding Sites Brain Cells Charge Cleaved cell Data Drug Targeting Electrodes Energy Transfer Engineering Ensure Frequencies G-Protein-Coupled Receptors Gated Ion Channel Goals Health Heart Human Kinetics Lanthanoid Series Elements Lead Length Ligand Binding Ligands Location Measures Membrane Potentials Membrane Proteins Modeling Movement Multiple Sclerosis Muscarinic Acetylcholine Receptor Muscarinic M2 Receptor Names Neurons Oocytes Play Positioning Attribute Potassium Potassium Channel Property Proteins Research Role Side Signal Transduction Site System Techniques Testing Therapeutic Transmembrane Domain Voltage-Clamp Technics Voltage-Gated Potassium Channel Xenopus oocyte base extracellular improved molecular dynamics monomer novel protein phosphatase inhibitor-2 public health relevance research study response sensor therapeutic target voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): This project has the goal of understanding the allosteric modulation, through voltage sensing, of voltage-gated ion channels and GPCRs has on their function. Allosteric modulation of voltage-gated ion channels occurs via domains not directly needed for voltage sensing and gating, that is, the first three transmembrane domains of each monomer, and the linker attaching this domain to the remainder of the protein. Allosteric modulation of GPCR activity occurs through voltage-sensing. Engineered versions of the Shaker potassium channel and the muscarinic acetylcholine receptor type 2 will be expressed in Xenopus oocytes and probed using electrophysiological and fluorescent techniques. The aims are to understand the role the linker between the third and fourth transmembrane domains of voltage-gated potassium channels plays in its function, to understand the movements that occur in the second and third transmembrane domains upon changes in membrane potential, independent of the movement of the primary voltage sensor in the fourth transmembrane domain, and to understand the movements that occur in response to changes in membrane potential in GPCRs. The long-term objectives of this project are to advance our understanding of potential novel targets for therapeutics targeted to modulate the voltage-sensing properties of voltage-gated ion channels and GPCRs. As these membrane proteins are already successful targets for many therapies, improved understanding of how to modulate their function should lead towards improvements of human health.

描述（由申请人提供）：该项目的目标是通过电压传感了解电压门控离子通道和 GPCR 的变构调制对其功能的影响。电压门控离子通道的变构调节通过电压传感和门控不直接需要的结构域发生，即每个单体的前三个跨膜结构域，以及将该结构域连接到蛋白质其余部分的连接体。 GPCR 活性的变构调节通过电压感应发生。 Shaker 钾通道和 2 型毒蕈碱乙酰胆碱受体的工程版本将在非洲爪蟾卵母细胞中表达，并使用电生理学和荧光技术进行探测。目的是了解电压门控钾通道第三和第四跨膜域之间的连接器在其功能中所起的作用，了解在膜电位变化时第二和第三跨膜域发生的运动，与运动无关的第四跨膜域中的初级电压传感器，并了解响应 GPCR 中膜电位变化而发生的运动。该项目的长期目标是增进我们对调节电压门控离子通道和 GPCR 的电压传感特性的潜在新治疗靶点的理解。由于这些膜蛋白已经成为许多疗法的成功靶标，因此更好地了解如何调节其功能应该有助于改善人类健康。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Real-time imaging of electrical signals with an infrared FDA-approved dye.

使用 FDA 批准的红外染料对电信号进行实时成像。

DOI：
10.1016/j.bpj.2014.07.054
发表时间：
2014-09-16
期刊：
Biophysical journal
影响因子：
3.4
作者：
Jeremy S. Treger;M. Priest;R. Iezzi;F. Bezanilla
通讯作者：
F. Bezanilla

Kv3.1 uses a timely resurgent K(+) current to secure action potential repolarization.

Kv3.1 使用及时复活的 K( ) 电流来确保动作电位复极化。

DOI：
发表时间：
2015-12-17
期刊：
影响因子：
16.6
作者：
Labro, Alain J;Priest, Michael F;Lacroix, Jérôme J;Snyders, Dirk J;Bezanilla, Francisco
通讯作者：
Bezanilla, Francisco

Thermal mechanisms of millimeter wave stimulation of excitable cells.

毫米波刺激可兴奋细胞的热机制。