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Genetic analysis to determine the functional role of GRID1

遗传分析以确定 GRID1 的功能作用

基本信息

批准号：
10217304
负责人：
Stephen F Traynelis
金额：
$ 15.6万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2022-04-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217304
关键词：
AMPA Receptors Affect Agonist Binding Binding Sites Brain Cations Cell Surface Receptors Communication Disease Distal Electrophysiology (science)Extracellular Domain Family member Frequencies Gene Family General Population Genes Glutamate Receptor Glutamates Glycine Health Human Individual Ion Channel Ions Kainic Acid Receptors Ligands Mediating Modality Molecular Conformation Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor A1 Neuraxis Neurologic Neurons Patients Physiological Play Population Population Genetics Process Property Proteins Regulation Role Serine Signal Transduction Site Synaptic Receptors Synaptic Transmission System Testing Variant constitutive active receptor delta receptors design dimer experimental study extracellular falls genetic analysis insight kainate mutant nervous system disorder neuropathology presynaptic receptor receptor binding response scaffold synaptogenesis web site

项目摘要

Summary The glutamate receptor gene family encodes AMPA, kainate, and NMDA receptors, which mediate excitatory synaptic transmission in the central nervous system. Two additional gene family members, GRID1 and GRID2, encode the enigmatic delta receptor GluD1 and GluD2 subunits, which can bind D-serine but do not appear to activate conventional signaling systems. There are four functional effects known for delta receptors: (1) Both delta receptors (GluD1 and GluD2) are activated when certain mutations occur in the transmembrane helices, which convert a non-gating receptor into a channel that is constitutively open, producing a tonic inward current. In addition, chimeric receptors in which the glutamate binding domain from a kainate or AMPA receptor replaces the analogous D-serine binding domain for GluD1 and GluD2 can be activated by glutamate, suggesting that the highly specialized machinery needed to convert agonist binding into pore opening is conserved in delta GluD1 receptors. (2) The binding of D-serine to GluD1 receptors harboring a TM3 mutation that renders them constitutively active can close the channel, raising that possibility that D-serine binding produces meaningful conformational changes with unknown physiological roles in WT receptors. (3) Ca2+ binding to a site at the dimer interface between two adjacent D-serine binding domains potentiates constitutive current in mutant receptors, suggesting Ca2+ could regulate GluD1 conformation and function. (4) The distal extracellular domain serves as a ligand for presynaptic Cbln2 and neurexin, which can alter synapse formation. Whereas Cbln2 and neurexin binding to GluD1 appears to be critical, it remains unclear whether channel gating, D-serine binding, or Ca2+ regulation of GluD1 play important roles in brain. A unique power of population genetics is that it can identify key functions of a protein in an unbiased manner. GRID1 is one of the least tolerant genes in the body, falling in the top 2 percentile for lacking variation, suggesting it plays essential roles. Consistent with this idea, patients with neurological conditions have been identified with missense variants in GRID1 that are absent in the general population. We will evaluate the effects of disease-associated variants in addition to well-tolerated variants commonly observed in the healthy population on three modalities associated with GRID1 function—constitutive activation, D-serine binding, Ca2+ binding. If any of these functional attributes are important, then we expect to find disease- associated variants that perturb them, while variants present in the standing population should be without effect. Three electrophysiological experiments will answer the following questions: Aim 1: Can missense variants produce active ion channels that are involved in neuropathology? Aim 2: Do missense variants alter the actions of D-serine and Ca2+ on constitutively active channels? Aim 3: Do missense variants alter the actions of glutamate on GluD1-GluK2 chimeric receptors?

总结