Structure and Function of NMDA Receptors

NMDA 受体的结构和功能

• 批准号: 9248017
• 负责人: Vasanthi Jayaraman
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248017
• 关键词: Address; Agonist; Alzheimer' s Disease; Binding; C-terminal; Cations; Cells; Chemicals; Communication; Complement; Complex; Data; Disease; Electrophysiology (science); Electrostatics; Extracellular Domain; Family; Foundations; Glutamate Receptor; Glutamates; Glycine; Image; Investigation; Ischemic Stroke; Learning; Length; Ligand Binding Domain; Maps; Measurement; Mediating; Mediator of activation protein; Memory; Molecular Conformation; Motion; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Neuraxis; Parkinson Disease; Pathway interactions; Physiological Processes; Proteins; Publishing; Roentgen Rays; Role; Schizophrenia; Seizures; Signal Pathway; Signal Transduction; Stroke; Structure; Sulfhydryl Compounds; Synaptic Transmission; Time; Translating; crosslink; dimer; glutamatergic signaling; inhibitor/antagonist; insight; luminescence resonance energy transfer; millisecond; molecular dynamics; mutant; nervous system disorder; painful neuropathy; public health relevance; receptor; receptor function; single-molecule FRET; transmission process

 DESCRIPTION (provided by applicant): N-methyl D-aspartate receptors are a subtype of glutamate receptors that mediate excitatory signal transmission in the mammalian central nervous system. Their primary function involves converting the chemical signal into an electrical signal, i.e. glutamate binding to an extracellular domain in the receptor triggers the formation of cation permeable transmembrane channels in the receptor. Given the importance of these receptors in mediating a number of physiological processes and the need to modulate their function in disease states, the primary questions are how does the agonist activate the protein and how can this mechanism be modulated. The NMDA receptors are modulator in structure consisting of an amino terminal domain, agonist binding domain, channel segments and the C-terminal domains. Here we propose to study the communication between the domains and their role in dictating activation and allosteric modulation. Specifically we will investigate the role o the interactions between GluN1 agonist binding domain with the GluN2 subunit in controlling agonist binding domain dynamics and extent of activation (specific aim 1) using a combination of luminescence resonance energy transfer, smFRET, and electrophysiology. We will also investigate the pathway for allosteric modulation by establishing the conformational changes starting at the amino terminal domain through the agonist binding domain and study the changes in dynamics in the extracellular domains during the allosteric modulation (specific aim 2). The spectroscopic investigations will be complemented by electrophysiological measurements investigating the changes in function induced by alterations at the interface between the domains. These functional and structural investigations will provide a comprehensive understanding of the conformational pathway as well as role of dynamics in activation and allosteric modulation in NMDA receptor function.



项目成果

Super-resolution mbPAINT for optical localization of single-stranded DNA.

• DOI: 10.1021/am403984k
• 发表时间: 2013-10-09
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Chen, Jixin;Bremauntz, Alberto;Kisley, Lydia;Shuang, Bo;Landes, Christy F.
• 通讯作者: Landes, Christy F.

Molecular approaches to chromatography using single molecule spectroscopy.

• DOI: 10.1021/ac5039225
• 发表时间: 2015-01-06
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Kisley, Lydia;Landes, Christy F.
• 通讯作者: Landes, Christy F.

High ionic strength narrows the population of sites participating in protein ion-exchange adsorption: a single-molecule study.

高离子强度缩小了参与蛋白质离子交换吸附的位点数量：单分子研究。

• DOI: 10.1016/j.chroma.2014.03.075
• 发表时间: 2014
• 期刊: Journal of chromatography. A
• 作者: Kisley,Lydia;Chen,Jixin;Mansur,AndreaP;Dominguez-Medina,Sergio;Kulla,Eliona;Kang,MarciK;Shuang,Bo;Kourentzi,Katerina;Poongavanam,Mohan-Vivekanandan;Dhamane,Sagar;Willson,RichardC;Landes,ChristyF
• 通讯作者: Landes,ChristyF

Fluorescence correlation spectroscopy study of protein transport and dynamic interactions with clustered-charge peptide adsorbents.

• DOI: 10.1002/jmr.2206
• 发表时间: 2012-08
• 期刊: JOURNAL OF MOLECULAR RECOGNITION
• 影响因子: 2.7
• 作者: Daniels, Charlisa R.;Kisley, Lydia;Kim, Hannah;Chen, Wen-Hsiang;Poongavanam, Mohan-Vivekanandan;Reznik, Carmen;Kourentzi, Katerina;Willson, Richard C.;Landes, Christy F.
• 通讯作者: Landes, Christy F.

Stargazin promotes closure of the AMPA receptor ligand-binding domain.

• DOI: 10.1085/jgp.201411287
• 发表时间: 2014-12
• 期刊: The Journal of general physiology
• 作者: MacLean DM;Ramaswamy SS;Du M;Howe JR;Jayaraman V
• 通讯作者: Jayaraman V