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Gating and permeation in ionotropic glutamate receptors

离子型谷氨酸受体的门控和渗透

基本信息

批准号：
9201660
负责人：
LONNIE P WOLLMUTH
金额：
$ 1.61万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201660
关键词：
AMPA Receptors Acute Address Affect Agonist Allosteric Site Beryllium Binding Biological Assay Brain Brain Diseases Charge Chronic Cysteine Development Disease Drug Design Dyes Elements Encephalopathies Epilepsy Gated Ion Channel Glutamate Receptor Glutamates Goals Health Human Inherited Internet Ion Channel Ions Knowledge Learning Ligand Binding Domain Maps Measures Mediating Missense Mutation Molecular Mutation N-Methyl-D-Aspartate Receptors Nervous System Physiology Nervous system structure Neurodevelopmental Disorder Neurotransmitter Receptor Neurotransmitters Outcome Pathway interactions Peripheral Pharmaceutical Preparations Physiological Physiology Positioning Attribute Property Receptor Activation Resolution Schizophrenia Signal Transduction Site Societies Specificity Steroids Structure Synapses Synaptic Transmission Thermodynamics Translating Variant channel blockers clinically significant crosslink developmental disease disease-causing mutation driving force drug of abuse excitotoxicity mind control mutant nervous system disorder neurotransmission neurotransmitter release operation polypeptide postsynaptic presynaptic receptor receptor function research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): The overall goal of my efforts is to define molecular features of synaptic transmission in the nervous system by studying the operation of NMDA and AMPA receptors. These receptors are neurotransmitter-gated ion channels that convert the presynaptic release of glutamate, the predominant excitatory neurotransmitter in the brain, into a postsynaptic signal. By defining the operation of NMDA and AMPA receptors, we will gain a better understanding of how they control brain function. We will also learn how to modulate their function with greater precision and specificity to help understand, and potentially treat, disease states such as schizophrenia, epilepsy, and the excitotoxicity associated with acute and chronic brain disorders. Our experiments will focus on structural elements of the NMDA and AMPA receptor located to the periphery of those lining the permeation pathway of the ion channel. Recent evidence has indicated that inherited and de novo mutations in these outer or peripheral structures induce developmental disorders and epileptic encephalopathies. These outer structures also contain allosteric sites for drugs of abuse and are targets for newly developed NMDA receptor modulators. Aim 1 will address the impact of the outer structures to the rapid and efficient pore opening that is the hallmark of fast synaptic transmission. For these experiments, we will combine single channel recordings with non-equilibrium conditions to define the energetics of displacement of the outer structures. Aim 2 will address how permeant ions access the central permeation pathway through the outer structures. Aim 3 will address how disease- causing mutations interact at the outer structures to alter NMDA and AMPA receptor function. Here, we will use cysteine cross-linking, fast agonist application, and agonist-free single channel recordings to address how specific elements interact in the outer structures to modulate receptor function. Overall our experiments will delineate how the outer structures contribute to the operation of NMDA and AMPA receptors. This information will aid in defining how disease-causing mutations affect receptor function and in developing specific therapies to target these receptors in nervous system disorders.