PP1 dephosphorylates GluN2B in the PDZ ligand to regulate synaptic NMDA receptor content

In this ongoing collaboration with Antonio Sanz-Clemente at Northwestern University, we define an additional mechanism regulating the synaptic expression of the GluN2B subunit of NMDA receptors.  Following synaptic activity, the GluN2B subunit is phosphorylated on the C-terminal PDZ ligand at S1480 but casein kinase 2 (CK2) resulting in the removal of GluN2B from the synapse. We now show that these extrasynaptic GluN2B subunits are dephosphorylated by PP1 in an activity-dependent manner resulting in the re-entry into the synapse.

See our paper at Cell Reports: https://doi.org/10.1016/j.celrep.2019.06.030

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Parallel non-ionotropic and ionotropic requirements for NMDA-mediated superoxide production

In this collaboration with the Swanson lab at UCSF, we show that NMDA-mediated superoxide production requires both a source of calcium influx and agonist binding to the glutamate site of the NMDA receptor (GluN2B subunit to be specific). Thus, both Ca2+ and agonist -binding are necessary, but neither is sufficient.  This is the first report demonstrating this dual requirement and I predict this will be rule rather than the exception for NMDA receptor function.



Intracellular MK801 does not fully block NMDA receptors

MK801 is an open-channel blocker of the NMDA receptor pore. That is, when the receptor is activated and the channel opens, MK801 enters the pore and blocks it. Usually, MK801 is used extracellularly, but multiple studies have included it in the intracellular pipette solution during whole-cell patch clamp recordings. We show here that MK801 has a much lower effective affinity for NMDA receptors when used intracellularly, suggesting caution is needed when interpreting such studies.

Welcome to new postdoc, Shekib Jami PhD

Shekib comes to us from Tom O’Dell’s lab at UCLA where he found unique NMDA receptor differences between ventral and dorsal hippocampus mediated by SK channels that account for differences in synaptic plasticity between those regions.  We’re excited to have Shekib as part of the team!

Welcome to rotating MD/PhD student Ariel Jacobi!

We are excited to have MD/PhD student Ariel Jacobi rotating in the lab. As an undergraduate, Ariel worked with David Lynch at UPenn examining the novel possibility of postsynaptic D-serine and its biosynthetic enzyme, serine racemase. She then spent a year at the Max Planck Institute for Brain Research in Germany studying turtle brains in the laboratory of Gilles Laurent. Let’s do some patching!


First Gray Lab SfN poster!

Jon presents his poster “Postsynaptic serine racemase regulates NMDA receptors” at this year’s Society for Neuroscience (SfN) meeting in Washington, DC. His poster drew a good audience including multiple luminaries in the field (e.g. Jon Johnson, U Pitt, seen here). Congrats Jon for a job well done!