Sanz-Clemente, A. . 1 , Gray, J. . 2 , Nicoll, R. 2 & Roche, K. 1
1 Receptor Biology Section. National Institute of Neurological Disorders and Stroke (NINDS/NIH)
2 Department of Cellular and Molecular Pharmacology. University of California San Francisco (UCSF)
Critical brain functions such as learning and memory rely heavily on accurate synaptic function and regulation. Glutamate receptor activity mediates synaptic transmission and its aberrant regulation is a shared hallmark of several neurological disorders. NMDA receptors (NMDARs) are glutamate-gated ion channels able to control synaptic plasticity and homeostasis by regulating calcium influx into the synapse. In cortex and hippocampus, functional NMDARs are tetramers composed of two GluN1 and two GluN2A or 2B subunits. Using a combination of molecular, pharmacological, immunocytochemical and electrophysiological approaches, we have investigated the regulation of NMDARs by casein kinase 2 (CK2). We have identified CK2-mediated phosphorylation of GluN2B (S1480) as a critical determinant for NMDAR trafficking. Specifically, this phosphorylation drives the removal of GluN2B from synapses via increased endocytosis, resulting in increased GluN2A synaptic expression. In addition, CK2-mediated phosphorylation controls the GluN2 subunit switch (from GluN2B-containing to GluN2A-containing NMDARs), which occurs during synaptic maturation and in response to activity. This evolutionally conserved process has important consequences in synaptic plasticity and intracellular signaling pathways. Finally, we have identified a new structural role for CaMKII, acting as a scaffolding protein that couples GluN2B and CK2 and regulates S1480 phosphorylation in response to activity. Collectively our data have provided new insight into the molecular mechanisms controlling NMDAR trafficking and synaptic function.