Structural basis of modulation of Na+ channels by local anesthetics
Structural basis of modulation of Na+ channels by local anesthetics
批准号:
8267695
负责人:
Baron Chanda
金额:
$42.21万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-08-01 至 2013-08-31
关键词:
Action PotentialsAddressAffectAffinityBehaviorBindingChargeCommunicationCouplesCouplingDNA Sequence RearrangementDevelopmentDiseaseEnvironmentFluorescenceFluorescence Resonance Energy TransferGated Ion ChannelGeneralized EpilepsyGoalsHealthHumanImmobilizationIndividualIon ChannelLabelLaboratoriesLeadLightLinkLocal AnestheticsLong QT SyndromeMapsMeasurementMeasuresMediatingMembrane PotentialsModelingMolecularMolecular ConformationMonitorMovementMuscleMutagenesisMutationMyotoniaNeuraxisPeptidesPersonal SatisfactionPharmaceutical PreparationsPhasePositioning AttributeProcessPropertyProteinsResearchRestScanningSignal TransductionSiteSodiumSodium ChannelSpecific qualifier valueStructureTestingTimeToxinTryptophanbasechannel blockersfluorophoremutantnext generationnovelpreventreceptorresearch studyresponsesensorvoltage
中文摘要
摘要
电信号是中枢神经系统的主要通讯方式之一,
电压依赖的钠通道负责启动电脉冲。存在NA通道
根据跨膜电压的不同,处于三种功能状态:关闭、打开和失活。基因突变
导致不完全失活的NA通道与各种疾病状况有关,包括
先天性QT间期延长综合征、全身性癫痫和肌强直。局麻药是一类
开放通道阻滞剂,用于治疗某些与通道相关的疾病,被认为是稳定的
处于停用状态的通道。我的实验室的长期目标是使用结构方法来
了解钠通道门控的物理基础及其调节。在这项研究中,我们建议
回答一个基本问题:像局部麻醉剂这样结合到通道孔上的分子是如何修饰的
离子通道的电压依赖门控行为。我们将使用特定地点的荧光记录
标记结合电生理测量以研究局麻药对脑电的影响
钠通道电压敏感S4段的构象变化。我们建议研究
A)局麻药对单个S4节段动力学的影响;b)局麻药对S4节段运动的影响
各个S4片段的结构,c)决定S4片段之间偶联的分子基础
以及d)确定是否将通道稳定在失活状态
支持局部麻醉剂捆绑。这些实验将根据最近阐明的
典型电压门控离子通道(Kv 1.2)的结构以了解Na通道的结构基础
门控及其局部麻醉剂的调节。叙事
为了开发更好的药物来治疗离子通道相关疾病,有必要
了解离子通道功能的结构基础。这里提出的研究利用了一种
相对新颖的结构方法研究钠通道的动力学及其局域调制
麻醉剂。这项研究将促进人类的健康和福祉,有助于
将以特定方式调节通道功能的下一代离子通道药物。
英文摘要
SUMMARY
Electrical signaling constitutes one of the primary means of communication in the central nervous system with
the voltage-dependent sodium channels being responsible for initiating electrical impulses. Na+ channels exist
in three functional states depending on transmembrane voltage: closed, open and inactivated. Mutations of
Na+ channels that lead to incomplete inactivation has been linked to various disease conditions including
congenital long QT syndrome, generalized epilepsy and muscle myotonia. Local anesthetics are a class of
open channel blockers that are used to treat some channel-associated conditions and are believed to stabilize
the channel in the inactivated state. The long term goal of my laboratory is to use structural approaches to
understand the physical basis of gating of Na+ channels and their modulation. In this study, we propose to
address a fundamental question: How do molecules like local anesthetics that bind to the channel pore modify
the voltage-dependent gating behavior of ion channels. We will use fluorescence recordings of site-specific
labels along with electrophysiological measurements to study the effect of local anesthetic on the
conformational changes associated with voltage-sensing S4 segments of Na+ channels. We propose to study
a) the effect of local anesthetic on the dynamics of individual S4 segments, b) the effect of local anesthetic on
structure of the individual S4 segments, c) determine the molecular basis of coupling between S4 segments
and local anesthetic binding at the pore, and d) determine if stabilizing the channel in the inactivated state
favors local anesthetic binding. These experiments will be interpreted in light of the recently elucidated
structure of a prototypical voltage-gated ion channel (Kv 1.2) to understand the structural basis of Na+ channel
gating and its modulation by local anesthetics. NARRATIVE
In order to develop better drugs to treat ion channel associated disease conditions, it becomes necessary to
understand the structural underpinnings of ion channel function. The research proposed here utilizes a
relatively novel structural approach to study the dynamics of the Na+ channel and its modulation by local
anesthetics. This research will advance human health and well-being by contributing to the development of
next generation of ion channel drugs that will modulate the channel function in a specified manner.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
TriMED: Measuring, Modeling and Manipulating Excitability and Disease
-
批准号:10627404
-
项目类别:
-
资助金额:$15.76万
-
财政年份:2023
-
负责人:Baron Chanda
-
依托单位:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
-
批准号:10266191
-
项目类别:
-
资助金额:$98.55万
-
财政年份:2020
-
负责人:Baron Chanda
-
依托单位:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
-
批准号:10225212
-
项目类别:
-
资助金额:$98.55万
-
财政年份:2020
-
负责人:Baron Chanda
-
依托单位:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
-
批准号:10609452
-
项目类别:
-
资助金额:$98.55万
-
财政年份:2020
-
负责人:Baron Chanda
-
依托单位:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
-
批准号:10400913
-
项目类别:
-
资助金额:$98.56万
-
财政年份:2020
-
负责人:Baron Chanda
-
依托单位:
Synthetic design of an all-optical electrophysiology system
-
批准号:10225934
-
项目类别:
-
资助金额:$15.14万
-
财政年份:2019
-
负责人:Baron Chanda
-
依托单位:
Mechanisms of voltage- and ligand-activation in HCN channels
-
批准号:10225052
-
项目类别:
-
资助金额:$11.49万
-
财政年份:2017
-
负责人:Baron Chanda
-
依托单位:
Thermodynamics and energetics of voltage-gated ion channels
-
批准号:8690188
-
项目类别:
-
资助金额:$31.89万
-
财政年份:2012
-
负责人:Baron Chanda
-
依托单位:
Thermodynamics and Energetics of voltage-gated ion channels
-
批准号:10226481
-
项目类别:
-
资助金额:$21.94万
-
财政年份:2012
-
负责人:Baron Chanda
-
依托单位:
Thermodynamics and energetics of voltage-gated ion channels
-
批准号:8544516
-
项目类别:
-
资助金额:$31.09万
-
财政年份:2012
-
负责人:Baron Chanda
-
依托单位:
Thermodynamics and energetics of voltage-gated ion channels
-
批准号:8422219
-
项目类别:
-
资助金额:$32.21万
-
财政年份:2012
-
负责人:Baron Chanda
-
依托单位:
Mechanisms of Gating in Voltage-dependent Sodium Channels
-
批准号:8584959
-
项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Mechanisms of Gating in Voltage-dependent Sodium Channels
-
批准号:9067359
-
项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Mechanisms of Gating in Voltage-dependent Sodium Channels
-
批准号:8852627
-
项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Structural basis of modulation of Na+ channels by local anesthetics
-
批准号:7666855
-
项目类别:
-
资助金额:$29.7万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Mechanisms of Gating in Voltage-dependent Sodium Channels
-
批准号:8723242
-
项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Structural basis of modulation of Na+ channels by local anesthetics
-
批准号:7439487
-
项目类别:
-
资助金额:$29.02万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Structural basis of modulation of Na+ channels by local anesthetics
-
批准号:8072740
-
项目类别:
-
资助金额:$42.21万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Structural basis of modulation of Na+ channels by local anesthetics
-
批准号:7917002
-
项目类别:
-
资助金额:$10.9万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
Structural basis of modulation of Na+ channels by local anesthetics
-
批准号:7860272
-
项目类别:
-
资助金额:$42.63万
-
财政年份:2008
-
负责人:Baron Chanda
-
依托单位:
海外基金