Structural and functional investigation of negative allosteric NMDA receptor modulation
负变构 NMDA 受体调节的结构和功能研究
基本信息
- 批准号:9317543
- 负责人:
- 金额:$ 31.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAffinityAgonistAphasiaBindingBinding SitesBrainBrain regionChildhoodComplementCrystallizationCrystallographyDataDevelopmentDimerizationDiseaseElectrophysiology (science)EngineeringEpilepsyEvaluationFrequenciesGenesGlutamate ReceptorGlutamatesGlycineHippocampus (Brain)InvestigationIon ChannelKidneyLaboratoriesLeadLigandsLinkMediatingMental disordersMolecular ConformationMutagenesisMutationMutation AnalysisN-Methyl-D-Aspartate ReceptorsNMDA receptor A1NMDA receptor antagonistNeuraxisNeurologicNeuronsParkinson DiseasePatientsPharmacologyPhysiologicalPlayPopulation HeterogeneityPropertyProteinsReceptor ActivationRett SyndromeRoleSiteSolubilityStructureSynapsesSynaptic TransmissionSynaptic plasticitySyndromeTestingTherapeuticTherapeutic AgentsWorkbasecell typeclinical developmentclinically relevantdimerdisulfide bondextracellulargain of functiongain of function mutationimprovedmembernervous system disorderneuron developmentneurophysiologyneurotransmissionnext generationnovelpatch clampreceptorreceptor functiontool
项目摘要
NMDA receptors (NMDARs) are glutamate receptor ion channels that mediate excitatory neurotransmission.
The majority of NMDARs are composed of two GluN1 and two GluN2 subunits. One GluN1 subunit has been
cloned, but there are four GluN2 subunits (GluN2A-D) that endow NMDARs with distinct functional properties
and different developmental and regional expression. Mutations in the gene encoding the GluN2A subunit have
been associated with childhood epilepsy/aphasia syndromes, and a subset of these mutations cause gain-of-
function in GluN2A-containing receptors that lead to severe neurologic complications. The high frequency of
GluN2A mutations linked to neurologic conditions provides a compelling rationale for the development of
GluN2A-selective therapeutic agents. GluN2A-selective modulators can also be useful and much needed
pharmacological tools for neurophysiological studies. We have identified novel GluN2A-selective negative
allosteric modulators (NAMs) that inhibit NMDARs by reducing glycine binding to the GluN1 subunit. These
NAMs can transform our ability to evaluate the contribution of GluN2A to normal brain function and disease. In
addition, we have determined crystal structures of the heterodimer formed by GluN1 and GluN2A agonist
binding domains (ABDs) with NAMs bound at the subunit interface. These crystal structures represent the
discovery of a novel, unexplored modulatory site and provide new opportunities for the development of subunit-
selective ligands. We will uncover structural and mechanistic features of this modulatory site and provide
important understanding required for the use of GluN2A-selective NAMs as pharmacological tools. Aim 1)
What are the structural bases for selectivity, potency, and efficacy of GluN2A-selective NAMs? We will use
crystallography, mutagenesis, and electrophysiological recordings of NMDA receptor function to define the
structural determinants for NAM inhibition. Aim 2) What is the mechanistic basis for allosteric interaction
between NAM and glycine binding sites? Crystallographic, pharmacological, and mutational analyses will
dissect the conformational changes and mechanism that causes the allosteric interaction between NAM and
glycine binding sites. Aim 3) Can GluN2A-selective NAMs inhibit triheteromeric and neuronal NMDA
receptors? We will define NAM inhibition of NMDARs in conditions relevant to synaptic transmission as well as
NAM inhibition of NMDARs that contain gain-of-function GluN2A mutations identified in epilepsy patients.
Neuronal NMDARs are heterogeneous populations of diheteromeric receptors comprised of two GluN1 and
two identical GluN2 subunits (e.g. GluN1/GluN2A) as well as triheteromeric receptors containing two GluN1
and two different GluN2 subunits (e.g. GluN1/GluN2A/GluN2B). Evaluation of GluN2A-selective modulators on
both diheteromeric and triheteromeric receptors is required for their use as pharmacological tools. In addition,
we will inhibit NMDAR-mediated synaptic currents in primary cultures of autaptic neurons that express different
ratios of GluN2A and GluN2B as well as autaptic neurons that express GluN2A with gain-of-function mutations.
NMDA受体(NMDARs)是介导兴奋性神经传递的谷氨酸受体离子通道。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kasper Boe Hansen其他文献
Kasper Boe Hansen的其他文献
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{{ truncateString('Kasper Boe Hansen', 18)}}的其他基金
Physiology and pharmacology of GluN3-containing NMDA receptors
含 GluN3 的 NMDA 受体的生理学和药理学
- 批准号:
10531915 - 财政年份:2021
- 资助金额:
$ 31.72万 - 项目类别:
Physiology and pharmacology of GluN3-containing NMDA receptors
含 GluN3 的 NMDA 受体的生理学和药理学
- 批准号:
10360476 - 财政年份:2021
- 资助金额:
$ 31.72万 - 项目类别:
Structural and functional investigation of allosteric NMDA receptor modulation
变构 NMDA 受体调节的结构和功能研究
- 批准号:
10365801 - 财政年份:2016
- 资助金额:
$ 31.72万 - 项目类别:
Structural and functional investigation of allosteric NMDA receptor modulation
变构 NMDA 受体调节的结构和功能研究
- 批准号:
10529334 - 财政年份:2016
- 资助金额:
$ 31.72万 - 项目类别:
Structural and functional investigation of negative allosteric NMDA receptor modulation
负变构 NMDA 受体调节的结构和功能研究
- 批准号:
9925846 - 财政年份:2016
- 资助金额:
$ 31.72万 - 项目类别:
Subproject Investigator: Kasper B. Hansen
子项目研究员:Kasper B. Hansen
- 批准号:
10004088 - 财政年份:2011
- 资助金额:
$ 31.72万 - 项目类别:
Subproject Investigator: Kasper B. Hansen
子项目研究员:Kasper B. Hansen
- 批准号:
9148613 - 财政年份:
- 资助金额:
$ 31.72万 - 项目类别:
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