Homeostatic control of the NMDA receptor co-agonist D-serine by SLC1A4

SLC1A4 对 NMDA 受体共激动剂 D-丝氨酸的稳态控制

基本信息

批准号：
9890859
负责人：
MICHAEL PATRICK KAVANAUGH
金额：
$ 40.5万
依托单位：
MC LAUGHLIN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890859
关键词：
Ablation Acute Affect Agonist Amino Acid Transporter Amino Acids Antibodies Behavior Binding Biological Assay Brain Brain Diseases Cells Cognitive Cognitive deficits Data Development Disease Disease model Electrophysiology (science)Family Family member Genes Genetic Glutamate Transporter Glutamates Glycine Homeostasis Human Human Engineering Hydroxyproline Impaired cognition Learning Link MCHR1 gene Measurement Measures Mediating Memory Molecular Mus Mutation N-Methyl-D-Aspartate Receptors NR1 gene Neuroanatomy Neurodevelopmental Deficit Neurodevelopmental Impairment Neutral Amino Acid Transport Systems Oocytes Pattern Pharmacology Physiological Physiology Play Process Property Radiolabeled Receptor Signaling Reporter Role Route Schizophrenia Serine Signal Transduction Site Slice Social Behavior Sodium Specificity Structure Synapses Synaptic Transmission Synaptic plasticity Testing Time Transgenic Mice Xenopus laevis diphenyl disease-causing mutation extracellular human disease inhibitor/antagonist mouse model nervous system disorder neurodevelopment novel paralogous gene pharmacophore radiotracer receptor receptor function reuptake solute theories uptake voltage clamp

项目摘要

NMDA receptors (NMDARs) participate in processes ranging from neural development to learning and memory. Disorders of NMDAR signaling are linked to several neurological diseases. Accumulating evidence suggests that the endogenous co-agonist D-serine plays a prominent role in activation of synaptic NMDARs in cortex. However, there are significant gaps in our understanding of the physiological mechanisms involved in D-serine homeostasis in brain and their potential impact on NMDAR signaling. Our preliminary data suggest that SLC1A4, a neutral amino acid transporter paralog within the SLC1 solute carrier family that includes glutamate transporters, unexpectedly mediates transmembrane flux of D-serine. We will test the hypotheses that SLC1A4 is in fact the major route of sodium-dependent D-serine uptake in brain and that selective SLC1A4 inhibitors developed from a hydroxyproline pharmacophore can alter D-serine homeostasis and thereby modulate NMDAR function and synaptic plasticity. We will also characterize the structure and function of a recently identified mutation in the human gene encoding SLC1A4 that is linked to neurodevelopmental and cognitive deficits, and we will create and study a transgenic mouse model of this human disease.

NMDA 受体 (NMDAR) 参与从神经发育到学习和记忆。 NMDAR 信号传导障碍与多种神经系统疾病有关疾病。越来越多的证据表明，内源性共激动剂 D-丝氨酸发挥着在皮层突触 NMDAR 的激活中发挥着重要作用。但仍存在显着差距帮助我们了解大脑中 D-丝氨酸稳态的生理机制及其对 NMDAR 信号传导的潜在影响。我们的初步数据表明 SLC1A4 SLC1 溶质载体家族中的中性氨基酸转运蛋白旁系同源物，包括谷氨酸转运蛋白，意外地介导 D-丝氨酸的跨膜通量。我们将测试假设 SLC1A4 实际上是钠依赖性 D-丝氨酸摄取的主要途径从羟脯氨酸药效团开发的选择性 SLC1A4 抑制剂可以改变 D-丝氨酸稳态，从而调节 NMDAR 功能和突触可塑性。我们还将表征最近在人类中发现的突变的结构和功能编码 SLC1A4 的基因与神经发育和认知缺陷有关，我们将创建并研究这种人类疾病的转基因小鼠模型。