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

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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.