Desensitization of Nicotinic Acetylcholine Receptors
Desensitization of Nicotinic Acetylcholine Receptors
批准号:
9378463
负责人:
Anthony L Auerbach
金额:
$31.63万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2021-04-30
关键词:
AgonistAmino AcidsBindingBinding SitesCellsCholinergic ReceptorsCouplingEquilibriumEventFree EnergyGated Ion ChannelGlobal ChangeGoalsHydrophobicityInvestigationIon ChannelIon Channel GatingKnowledgeLigandsLocationMeasuresMembrane ProteinsMethodsMicroscopicMolecularMolecular ConformationMuscleMutationNerveNeurotransmitter ReceptorNeurotransmittersNicotinic ReceptorsPathway interactionsPatternPharmacologyPhysiologicalPositioning AttributePotential EnergyProbabilityProcessProlineRecoveryRefractorySpeedStructureSurfaceSynapsesSynaptic ReceptorsTestingTransmembrane Domaindesensitizationexperimental studyinterestmutantoperationpreventreceptorresponsevoltage
中文摘要
神经-肌肉突触的烟碱型乙酰胆碱受体(AChRs)进入和恢复
D(敏感)状态,在神经递质持续存在的情况下保持不活跃。
受体脱敏下调细胞反应,并编码长期活动模式。
我们的目标是在分子水平上了解AChR的脱敏过程。最重要的
D态如何连接到C(丢失的)和O(PEN)选通态的问题仍然没有解决。
我们将研究两个假设:i)D、O和C在闭合循环中相连,而ii)D不相连
连接到C或O,而不是连接到短暂的门控中间状态。我们将测试
第二个假设是通过使用突变和电压来移动点
门控和减敏构象变化通路之间的分叉,指向C to
在恢复时产生开口或朝向O方向,以防止开口。许多氨基酸会发生变化
在AChR门控和脱敏转变期间的结构,以及这些微观结构中的每一个
重排有一个相关的,而且主要是局部的自由能变化。我们将衡量这些指标
AChR跨膜区两个区域脱敏的能量变化:i)a
M_1和II)疏水性M_2门中的Pro扭结。尽管进行了密集的调查,但
AChR脱敏的分子基础自AChR脱敏第一次以来一直不清楚
描述于60年前。这项提案中的实验将填补我们在
了解受体的工作原理。
英文摘要
Nicotinic acetylcholine receptors (AChRs) at the nerve-muscle synapse enter and recover from
D(esensitized) states that remain inactive in the continuous presence of neurotransmitter.
Receptor desensitization down-regulates cell responses and encodes long-term activity patterns.
Our goal is to understand the AChR desensitization process at a molecular level. The essential
problem of how D states are connected to C(losed) and O(pen) gating states remains unsolved.
We will investigate two hypotheses: i) D, O and C are connected in a closed cycle and ii) D is not
connected either to C or O but rather to a short-lived gating intermediate state. We will test the
second hypothesis experimentally by using mutations and voltage to shift the point of
bifurcation between gating and desensitization conformational-change pathways, towards C to
produce openings upon recovery or towards O to prevent openings. Many amino acids change
structure during the AChR gating and desensitization transitions, and each of these microscopic
rearrangements has an associated and mostly-local free energy change. We will measure these
energy changes in desensitization at two regions in the AChR transmembrane domain: i) a
proline kink in M1 and ii) the hydrophobic M2 gate. Despite intensive investigation, the
molecular basis of AChR desensitization has remained obscure since the process was first
described 60 years ago. The experiments in this proposal will fill this substantial gap in our
understanding of receptor operation.
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Desensitization of Nicotinic Acetylcholine Receptors
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批准号:9920740
-
项目类别:
-
资助金额:$53.77万
-
财政年份:2017
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负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
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批准号:8506185
-
项目类别:
-
资助金额:$49.83万
-
财政年份:2009
-
负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
-
批准号:8470723
-
项目类别:
-
资助金额:$32.45万
-
财政年份:2009
-
负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
-
批准号:8074901
-
项目类别:
-
资助金额:$33.63万
-
财政年份:2009
-
负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
-
批准号:8269918
-
项目类别:
-
资助金额:$33.63万
-
财政年份:2009
-
负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
-
批准号:7728812
-
项目类别:
-
资助金额:$33.49万
-
财政年份:2009
-
负责人:Anthony L Auerbach
-
依托单位:
Engineering a Transmitter Binding Site
-
批准号:9270608
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项目类别:
-
资助金额:$48.43万
-
财政年份:2009
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负责人:Anthony L Auerbach
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依托单位:
MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS
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批准号:6363906
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项目类别:
-
资助金额:$19.5万
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财政年份:1998
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负责人:Anthony L Auerbach
-
依托单位:
Molecular Mechanisms of Glutamate Receptor Channels
-
批准号:6831650
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项目类别:
-
资助金额:$35.71万
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财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
Molecular Mechanisms of Glutamate Receptor Channels
-
批准号:7173258
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项目类别:
-
资助金额:$33.82万
-
财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
Molecular Mechanisms of Glutamate Receptor Channels
-
批准号:6727961
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项目类别:
-
资助金额:$33.96万
-
财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS
-
批准号:2622983
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项目类别:
-
资助金额:$17.82万
-
财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
Molecular Mechanisms of Glutamate Receptor Channels
-
批准号:6984148
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项目类别:
-
资助金额:$34.85万
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财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS
-
批准号:6165522
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项目类别:
-
资助金额:$18.93万
-
财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS
-
批准号:2883722
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项目类别:
-
资助金额:$18.38万
-
财政年份:1998
-
负责人:Anthony L Auerbach
-
依托单位:
MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS
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批准号:6531071
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项目类别:
-
资助金额:$20.08万
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财政年份:1998
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负责人:Anthony L Auerbach
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依托单位:
MULTIPLE ACTIVITY PATTERNS OF ACETYLCHOLINE RECEPTORS
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批准号:3407095
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项目类别:
-
资助金额:$8.55万
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财政年份:1987
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负责人:Anthony L Auerbach
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依托单位:
MULTIPLE ACTIVITY PATTERNS OF ACETYLCHOLINE RECEPTORS
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批准号:3407096
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项目类别:
-
资助金额:$6.86万
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财政年份:1987
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负责人:Anthony L Auerbach
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依托单位:
MULTIPLE ACTIVITY PATTERNS OF ACETYLCHOLINE RECEPTORS
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批准号:2891676
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项目类别:
-
资助金额:$36.69万
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财政年份:1987
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负责人:Anthony L Auerbach
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依托单位:
Multiple Activity Patterns of Acetylcholine Receptors
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批准号:8442323
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项目类别:
-
资助金额:$58.06万
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财政年份:1987
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负责人:Anthony L Auerbach
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依托单位:
海外基金