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

项目摘要 cAMP信号在突触可塑性和记忆中起着关键作用。β 2肾上腺素能受体（β2AR） 与AMPAR形成独特的信号复合物，该复合物还包括Gs、腺苷酸环化酶（AC）和cAMP- 依赖性激酶去甲肾上腺素（NE）通过β 2 AR-cAMP - PKA刺激AMPAR的磷酸化 GluA 1亚单位在S845上，促进AMPAR运输到突触后膜。一个主要的机制， 突触传递的长时程增强（LTP）是学习和记忆的基础， 在突触后的位置。磷酸二酯酶4家族（PDE 4A-D）成员抑制cAMP信号传导 通过水解cAMP。睡眠剥夺刺激PDE 4A异构体PDE 4A 5的表达， 海马长时程增强（LTP）和PDE 4A 5的敲低挽救了学习缺陷。因此，我们认为， PDE 4A 5的药理学靶向可以减轻脑疾病中的认知缺陷。在目标1中，我们发现， PDE 4A 5以其独特的~100个氨基酸长的N-末端（NT）结合PSD-95的SH 3结构域。PSD-95 锚定AMPAR。在我的博士学位剩下的时间里。我建议定义PDE 4A 5的功能作用及其 与PSD-95在AMPAR受体运输中的相关性。对于目标2，我在另一个实验室的博士后职位，我 考虑通过采用先进的cAMP信号和超成像方法来扩展该项目 突触后纳米结构域中AMPAR定位的分辨率分析。

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.