GABAA Receptor-interacting Proteins

GABAA 受体相互作用蛋白

基本信息

批准号：
7983404
负责人：
ANGEL L DE BLAS
金额：
$ 33.47万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983404
关键词：
Affect Anesthesia procedures Antibodies Anxiety Autistic Disorder Binding Brain Cell Adhesion Molecules Cells Clinic Complex Cytoplasmic Tail Development Disease Drug usage Electron Microscopy Embryo Epilepsy Extracellular Domain Family Figs - dietary Grant Guanine Nucleotide Exchange Factors Hippocampus (Brain)Individual Knowledge Link Maintenance Mental Depression Mental disorders Neurons Neurotransmitters Play Presynaptic Terminals Process Protein Isoforms Proteins RNA Interference Regulation Reporting Role SH3 Domains Schizophrenia Signal Transduction Sleep Disorders Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Therapeutic Time collybistin density design gamma-Aminobutyric Acid gephyrin human RIPK1 protein immunocytochemistry light microscopy member multicatalytic endopeptidase complex nervous system disorder neuronal survival overexpression postnatal postsynaptic receptor research study rho synaptic function synaptogenesis transmission process ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): There is limited knowledge about the mechanisms by which GABAA receptors and other postsynaptic molecules concentrate at GABAergic synapses. GABAergic synapses are mostly inhibitory and play a major role in brain function. The long-term objective of this proposal is to identify the mechanisms involved in the postsynaptic clustering and anchoring of GABAA receptors and other postsynaptic molecules at GABAergic synapses. This proposal aims to 1) study the role of collybistin and gephyrin in regulating postsynaptic GABAA receptor clustering; 2) to study the role of protocadherin cell adhesion molecules in GABAergic synapses and 3) to study the role that a newly identified GABAA receptor-interacting protein plays in the clustering of the postsynaptic GABAA receptors. Light microscopy and electron microscopy immunocytochemistry with specific antibodies will be used for revealing the synaptic localization and clustering of GABAA receptors and postsynaptic proteins in the intact brain and in hippocampal cultures. Techniques such as RNAi and the expression of tagged postsynaptic proteins in cultured hippocampal neurons and in the intact brain will also be used. These studies are relevant for understanding the mechanisms involved in the synaptic targeting and postsynaptic clustering of GABAA receptors and GABAergic synaptic plasticity. It is predicted that the inappropriate postsynaptic clustering and localization of GABAA receptors would pathologically affect GABAergic synaptic function and brain development, leading to epilepsy and other neurological and mental disorders. PUBLIC HEALTH RELEVANCE: GABA is the main inhibitory neurotransmitter in the brain. The postsynaptic GABAA receptors and associated proteins play a fundamental role in the inhibitory synaptic transmission. Pathological alteration of GABAergic transmission has been linked to neurological and mental disorders including epilepsy, anxiety, depression, schizophrenia, autism and sleep disorders, among others. GABAA receptors are also the target of several therapeutic drugs used in the clinic and in anesthesia. Our proposed studies on the postsynaptic molecules involved in the clustering of GABAA receptors will be relevant for a better understanding of the mechanisms that control the assembly and normal function of GABAergic synapses and for designing strategies aimed to the amelioration of the diseases involving pathological alterations of these synapses.

描述（由申请人提供）：关于GABAA受体和其他突触后分子集中于GABA能突触的机制的知识有限。 GABA能突触大多是抑制性的，在大脑功能中起主要作用。该提案的长期目标是确定GABAA受体和其他突触后分子在GABA能突触中涉及的机制。该提案的目的是1）研究Collybistin和Gephyrin在调节突触后GABAA受体聚类中的作用； 2）研究原粘蛋白细胞粘附分子在GABA能突触中的作用，3）研究了新鉴定的GABAA受体相互作用蛋白在突触后GABAA受体聚类中发挥作用的作用。光学显微镜和电子显微镜免疫细胞化学具有特定抗体将用于揭示完整大脑和海马培养物中GABAA受体和突触后蛋白的突触定位和聚类。也将使用培养的海马神经元和完整大脑中标记的突触后蛋白的技术和标记的突触后蛋白的表达。这些研究与理解GABAA受体的突触靶向和突触后聚类的机制有关。据预测，GABAA受体的突触后聚类和定位将在病理上影响GABA能突触功能和大脑发育，从而导致癫痫以及其他神经系统疾病。公共卫生相关性：GABA是大脑中主要的抑制性神经递质。突触后GABAA受体和相关蛋白在抑制性突触传播中起着基本作用。 GABA能传播的病理改变与神经和精神障碍有关，包括癫痫，焦虑，抑郁，精神分裂症，自闭症和睡眠障碍等。 GABAA受体也是诊所和麻醉中使用的几种治疗药物的靶标。我们提出的关于与GABAA受体聚类有关的突触后分子的研究将与更好地理解控制GABAergic突触的组装和正常功能的机制有关，并设计涉及涉及这些突触病理学改变的疾病的策略。