Casein Kinase 2 Regulates the NR2 Subunit Composition of Synaptic NMDA Receptors

Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.05). 09/2010; 67(6):984-96. DOI: 10.1016/j.neuron.2010.08.011
Source: PubMed


N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a central role in development, synaptic plasticity, and neurological disease. NMDAR subunit composition defines their biophysical properties and downstream signaling. Casein kinase 2 (CK2) phosphorylates the NR2B subunit within its PDZ-binding domain; however, the consequences for NMDAR localization and function are unclear. Here we show that CK2 phosphorylation of NR2B regulates synaptic NR2B and NR2A in response to activity. We find that CK2 phosphorylates NR2B, but not NR2A, to drive NR2B-endocytosis and remove NR2B from synapses resulting in an increase in synaptic NR2A expression. During development there is an activity-dependent switch from NR2B to NR2A at cortical synapses. We observe an increase in CK2 expression and NR2B phosphorylation over this same critical period and show that the acute activity-dependent switch in NR2 subunit composition at developing hippocampal synapses requires CK2 activity. Thus, CK2 plays a central role in determining the NR2 subunit content of synaptic NMDARs.

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Available from: Antonio Sanz-Clemente, May 28, 2014
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    • "Posttranslational modifications can alter how strongly GluN2A and GluN2B subunits bind to these PSD proteins, and this is one mechanism that regulates the availability of these subunits at the synapse: in turn this could influence the induction of plasticity. For example, Cdk2 phosphorylates GluN2B at Ser1480, which disrupts its interaction with PSD-95 and SAP102 and leads to a reduction in synaptic GluN2B [40,41]. Not only is this phosphorylation event unique to GluN2B [41], it is also regulated by synaptic activity [40]. "
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    ABSTRACT: N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130163. DOI:10.1098/rstb.2013.0163 · 7.06 Impact Factor
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    • "For example, in culture systems, endocytic removal of GluN3A is regulated by PACSIN1/syndapin1 (Pé rez- Otañ o et al., 2006). PACSIN contains several potential phosphorylation sites for PKC and casein kinase 2 (Plomann et al., 1998), both of which are implicated in NMDAR subunit regulation (Sanz-Clemente et al., 2010). Since mGluR1 activation drives the removal of GluN3A-containing and the insertion of GluN2A-con- taining NMDARs via a Ca 2+ -dependent pathway, it will be of interest to investigate whether mGluR1 activation recruits PACSIN to promote GluN3A endocytosis. "
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    ABSTRACT: Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction.
    Neuron 10/2013; 80(4). DOI:10.1016/j.neuron.2013.07.050 · 15.05 Impact Factor
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    • "phosphorylation events induced by ligand-binding and during the synapse maturation [19]. The serine phosphorylation within ESDV motif of NR2B (S1480) by casein kinase II (CKII) leads to an increased endocytosis rate of the NR2B subunit [20,21]. However, tyrosine phosphorylation within the YEKL motif of NR2B (Y1472) by Fyn kinase [22] has been demonstrated to inhibit the internalization of the NR2B subunit [23,24]. "
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    ABSTRACT: The N-methyl-D-aspartate receptors are key mediators of excitatory transmission and are implicated in many forms of synaptic plasticity. These receptors are heterotetrameres consisting of two obligatory NR1 and two regulatory subunits, usually NR2A or NR2B. The NR2B subunits are abundant in the early postnatal brain, while the NR2A/NR2B ratio increases during early postnatal development. This shift is driven by NMDA receptor activity. A functional interplay of the Low Density Lipoprotein Receptor Related Protein 1 (LRP1) NMDA receptor has already been reported. Such abilities as interaction of LRP1 with NMDA receptor subunits or its important role in tPa-mediated NMDA receptor signaling were already demonstrated. Moreover, mice harboring a conditional neuronal knock-out mutation of the entire Lrp1 gene display NMDA-associated behavioral changes. However, the exact role of LRP1 on NMDA receptor function remains still elusive. To provide a mechanistic explanation for such effects we investigated whether an inactivating knock-in mutation into the NPxY2 motif of LRP1 might influence the cell surface expression of LRP1 and NMDA receptors in primary cortical neurons. Here we demonstrate that a knock-in into the NPxY2 motif of LRP1 results in an increased surface expression of LRP1 and NR2B NMDA receptor subunit due to reduced endocytosis rates of LRP1 and the NR2B subunit in primary neurons derived from LRP1DeltaNPxY2 animals. Furthermore, we demonstrate an altered phosphorylation pattern of S1480 and Y1472 in the NR2B subunit at the surface of LRP1DeltaNPxY2 neurons, while the respective kinases Fyn and casein kinase II are not differently regulated compared with wild type controls. Performing co-immunoprecipitation experiments we demonstrate that binding of LRP1 to NR2B might be linked by PSD95, is phosphorylation dependent and this regulation mechanism is impaired in LRP1DeltaNPxY2 neurons. Finally, we demonstrate hyperactivity and changes in spatial and reversal learning in LRP1DeltaNPxY2 mice, confirming the mechanistic interaction in a physiological readout. In summary, our data demonstrate that LRP1 plays a critical role in the regulation of NR2B expression at the cell surface and may provide a mechanistic explanation for the behavioral abnormalities detected in neuronal LRP1 knock-out animals reported earlier.
    Molecular Neurodegeneration 07/2013; 8(1):25. DOI:10.1186/1750-1326-8-25 · 6.56 Impact Factor
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