Role of PSD-95-linked PDE4A5 in Regulation of AMPA Receptors

PSD-95 连接的 PDE4A5 在 AMPA 受体调节中的作用

基本信息

批准号：
10829146
负责人：
Zoila Maribel Estrada-Tobar
金额：
$ 4.13万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10829146
关键词：
A kinase anchoring protein AMPA Receptors Acute Adenylate Cyclase Adrenergic Receptor Affect Agonist Amino Acids Binding Biological Assay Brain Diseases Cattle Cell Culture Techniques Chimeric Proteins Co-Immunoprecipitations Cognitive deficits Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases DLG4 gene Detection Disease Doctor of Philosophy Ectopic Expression Excision Family Fluorescence Polarization Fluorescent Antibody Technique Fostering Glutamate Receptor Goals Hippocampus Human Image Imaging Techniques Impairment In Vitro Isomerism Label Learning Link Long-Term Potentiation Major Depressive Disorder Mediating Membrane Memory Memory impairment Molecular Monitor Neurons Norepinephrine Pharmacologic Substance Phase Phosphorylation Phosphotransferases Play Positioning Attribute Postdoctoral Fellow Postsynaptic Membrane Process Protein Isoforms Proteins Psyche structure Regulation Repression Research Rodent Role SH3 Domains Signal Transduction Site Sleep Deprivation Structural Protein Structure Surface Synapses Synaptic Transmission Synaptic plasticity Testing Work comparison control falls genetic regulatory protein imaging modality in vivo knock-down member nano nervous system disorder novel optical sensor optogenetics pharmacologic phosphodiesterase IV phosphoric diester hydrolase polypeptide post-doctoral training postsynaptic receptor reconstitution sensor superresolution microscopy tool trafficking ultra high resolution

项目摘要

PROJECT SUMMARY Signaling by cAMP plays a critical role in synaptic plasticity and memory. The b2-adrenergic receptor (β2AR) forms a unique signaling complex with AMPARs that also includes Gs, adenylyl cyclase (AC), and the cAMP- dependent kinase. Norepinephrine (NE) stimulates via β2AR -cAMP - PKA the phosphorylation of the AMPAR GluA1 subunit on S845, promoting AMPAR trafficking to the postsynaptic membrane. A primary mechanism of long-term potentiation (LTP) of synaptic transmission, which underlies learning and memory, is the accumulation of AMPAR at the postsynaptic site. Members of the Phosphodiesterase 4 family (PDE4A-D) curb cAMP signaling by hydrolyzing cAMP. Sleep deprivation stimulates expression of the PDE4A isomer PDE4A5, which impairs hippocampal long-term potentiation (LTP) and knock down of PDE4A5 rescues learning deficits. Therefore, pharmacological targeting of PDE4A5 may alleviate cognitive deficits in brain disorders. In Aim 1, we found that PDE4A5 binds with its unique ~100 amino acid long N-terminus (NT) to the SH3 domain of PSD-95. PSD-95 anchors AMPARs. For the remainder of my PhD. I propose to define the functional role of PDE4A5 and its association with PSD-95 in AMPAR receptor trafficking. For Aim 2, my postdoctoral position in another lab, I consider expanding this project by employing advanced imaging methods for cAMP signaling and super resolution analysis of AMPAR localization in postsynaptic nanodomains.

项目摘要营地信号传导在突触可塑性和记忆中起关键作用。 B2-肾上腺素受体（β2AR）形成具有AMPAR的独特信号复合物，其中还包括GS，腺苷酸环化酶（AC）和CAMP- 依赖性激酶。去甲肾上腺素（NE）通过β2AR-CAMP -PKA刺激AMPAR的磷酸化 S845上的GLUA1亚基，促进了AMPAR贩运到突触后膜。主要机制基础学习和记忆的突触传播的长期增强（LTP）是积累在突触后地点的AMPAR。磷酸化酶酶4家族（PDE4A-D）遏制cAMP信号的成员通过水解营。睡眠剥夺刺激PDE4A异构体PDE4A5的表达，这会损害海马长期增强（LTP）和击倒PDE4A5救援学习缺陷。所以， PDE4A5的药理学靶向可以减轻脑疾病的认知防御能力。在AIM 1中，我们发现 PDE4A5与其独特的〜100氨基酸长N端（NT）结合了PSD-95的SH3结构域。 PSD-95 锚点Ampars。在我的其余博士学位上。我建议定义PDE4A5及其的功能作用在AMPAR受体运输中与PSD-95相关。对于AIM 2，我在另一个实验室中的博士后职位，我考虑通过采用高级成像方法来扩展该项目，并进行超级在突触后纳米构中的AMPAR定位的分辨率分析。