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

• 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
• 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

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.

项目总结 CAMP信号在突触可塑性和记忆中起着关键作用。B2-肾上腺素能受体(β2AR) 与AMPAR形成独特的信号复合体，还包括Gs、腺苷环化酶(AC)和cAMP- 依赖的激酶。去甲肾上腺素通过β-2AR-cAMP-PKA刺激AMPAR的磷酸化 S845上的GluA1亚基，促进AMPAR转运到突触后膜。一种主要的机制 突触传递的长时程增强(LTP)是学习和记忆的基础，是积累 突触后部位的AMPAR。磷酸二酯酶4家族成员(PDE4A-D)抑制cAMP信号 通过水解cAMP。睡眠剥夺刺激PDE4A异构体PDE4A5的表达，从而损害 海马长时程增强(LTP)和PDE4A5的敲除挽救了学习障碍。因此， PDE4A5的药理靶向可能缓解脑疾病的认知障碍。在目标1中，我们发现 PDE4A5与PSD-95的SH3结构域结合，结合其独特的~100个氨基酸N末端(NT)。PSD-95 锚定AMPAR。在我剩余的博士学位上。我建议定义PDE4A5的功能作用及其 与PSD-95在AMPAR受体转运中的关系对于目标2，我在另一个实验室的博士后职位，我 考虑通过使用先进的cAMP信号和超级成像方法来扩展该项目 突触后纳米域内AMPAR定位的分辨率分析。