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

• 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
• 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

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）参与从神经发育到神经发育的过程。 学习和记忆。NMDAR信号传导障碍与几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-丝氨酸起作用， 在皮层中的突触NMDAR的激活中的突出作用。然而， 在我们对脑中D-丝氨酸稳态的生理机制的理解中， 以及它们对NMDAR信号传导的潜在影响。我们的初步数据表明，SLC 1A 4， SLC 1溶质载体家族中的中性氨基酸转运蛋白，包括 谷氨酸转运蛋白，意想不到地介导D-丝氨酸的跨膜通量。我们将测试 假设SLC 1A 4实际上是钠依赖性D-丝氨酸摄取的主要途径， 脑，并且从羟脯氨酸药效团开发的选择性SLC 1A 4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 还将描述最近在人类中发现的突变的结构和功能。 基因编码SLC 1A 4与神经发育和认知缺陷，我们将 创建并研究这种人类疾病的转基因小鼠模型。