Actions of proline at receptors and synapses

脯氨酸对受体和突触的作用

基本信息

批准号：
10669270
负责人：
STEVEN J TAVALIN
金额：
$ 23.1万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669270
关键词：
Acute Affect Affinity Amino Acids Behavior Disorders Behavioral Brain Brain region Cells Central Nervous System Cognition Disorders Degradation Pathway Development Disease Dose Electrophysiology (science)Epilepsy Equilibrium Glutamate Agonist Glutamate Receptor Glutamates Hippocampus Imaging Techniques In Situ Intellectual functioning disability Knowledge Link Mediating Mental Depression Mental disorders Methods Molecular N-Methylaspartate Nervous System Neurologic Neurons Neurotransmitters Neutral Amino Acids Population Presynaptic Terminals Proline Proteins Receptor Activation Recombinants Risk Factors Schizophrenia Shapes Site Synapses Synaptic Receptors Synaptic Transmission Synaptic plasticity Testing Transfection autism spectrum disorder cell type imaging modality immunocytochemistry information processing inhibitor mental set mind control nervous system disorder neuron development neurotransmission novel therapeutic intervention patch clamp pharmacologic postsynaptic postsynaptic neurons proline permease promoter protein expression receptor response transmission process uptake

项目摘要

Disturbances in brain handling of the amino acid proline are linked to a wide variety neurological and behavioral disorders including schizophrenia, autism, epilepsy, intellectual disability, and depression. Although proline has been suggested to be a candidate neurotransmitter, a demonstration of a prolinergic component of synaptic has been lacking. Proline is thought to mediate its action, in part, via activation of ionotropic glutamate receptors, which mediate the majority of synaptic transmission in the central nervous system. Yet, the actions of proline at glutamate receptors and synaptic transmission are not well understood. We hypothesize that the proline sensitivity of ionotropic glutamate receptors varies with subunit composition. Moreover, we propose that prolinergic transmission can be demonstrated by pharmacologically probing transmission between neurons that express SLC6A7, the high-affinity proline transporter responsible for a majority of synaptic proline uptake, and its postsynaptic partners. We will use a combination of electrophysiological, molecular, immunocytochemical, and imaging methods we will examine: 1) the pharmacological profile of proline at recombinant ionotropic glutamate receptors with distinct subunit compositions; 2) the preferred hippocampal cell types that are targets of putative prolinergic neurons; and 3) the how synaptically evoked proline accumulations shape glutamatergic transmission. Collectively, these studies will fill in major gaps in our knowledge regarding the actions of proline at glutamate receptors and synapses where prolinergic transmission likely occurs.

大脑处理氨基酸脯氨酸的障碍与多种神经系统和疾病有关。行为障碍，包括精神分裂症、自闭症、癫痫、智力障碍和抑郁症。虽然脯氨酸被认为是一种候选神经递质，证明了脯氨酸能成分突触一直缺乏。脯氨酸被认为部分通过离子型谷氨酸的激活来介导其作用受体，介导中枢神经系统中的大部分突触传递。然而，谷氨酸受体上的脯氨酸和突触传递尚不清楚。我们假设离子型谷氨酸受体的脯氨酸敏感性随亚基组成而变化。此外，我们建议脯氨酸传递可以通过药理学探测神经元之间的传递来证明，表达 SLC6A7，负责大部分突触脯氨酸摄取的高亲和力脯氨酸转运蛋白，以及它的突触后伙伴。我们将结合使用电生理学、分子学、免疫细胞化学、我们将检查和成像方法：1) 重组离子型脯氨酸的药理学特征具有不同亚基组成的谷氨酸受体； 2) 作为目标的首选海马细胞类型假定的脯氨酸能神经元； 3）突触诱发的脯氨酸积累如何形成谷氨酸能传播。总的来说，这些研究将填补我们关于脯氨酸作用的知识空白在可能发生脯氨酸能传递的谷氨酸受体和突触处。