Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus

Abstract

Synaptic plasticity is the foundation of learning and memory. The protein kinase CK2 phosphorylates many proteins related to synaptic plasticity, but whether it is directly involved in it has not been clarified. Here, we examined the role of CK2 in synaptic plasticity in hippocampal slices using the CK2 selective inhibitors 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) and 4,5,6,7-tetrabromobenzotriazole (TBB). These significantly inhibited N -methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP). DRB also inhibited NMDA receptor-mediated synaptic transmission, while leaving NMDA receptor-independent LTP unaffected. NMDA receptors thus appear to be the primary targets of CK2. Although both long-term depression (LTD) and LTP are induced by the influx of Ca 2+ through NMDA receptors, surprisingly, LTD was not affected by CK2 inhibitors. We postulated that the LTP-selective modulation by CK2 is due to selective modulation of NMDA receptors, and tested two hypotheses concerning the modulation of NMDA receptors: (i) CK2 selectively modulates NR2A subunits possibly related to LTP, but not NR2B subunits possibly related to LTD; and (ii) CK2 selectively affects synaptic but not extrasynaptic NMDA receptors whose activation is sufficient to induce LTD. DRB decreased NMDA receptor-mediated synaptic transmission in the presence of selective NR2A subunit antagonist. The former hypothesis thus appears unlikely to be correct. However, DRB decreased synaptic NMDA receptor responses in cultured hippocampal neurons without affecting extrasynaptic NMDA receptor current. These findings support the latter hypothesis, that CK2 selectively affects LTP by selective modification of synaptic NMDA receptors in a receptor-location-specific manner.

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

“…It is not clear what function CK2 is performing at synapses, but increasing evidence suggests a role in learning and memory. For example, LTP can be blocked by CK2 inhibitors (5,6-dichloro-1-β-D-ribofuranosyl-benzimidazole - DRB - and TBB) by reducing NMDAR activity (Kimura and Matsuki, 2008). Furthermore, DRB is able to reduce fear-motivated learning (Igaz et al, 2002).…”

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords

“…To determine the role of NR2A and NR2B subunits in the increased glutamate release to dorsal horn neurons induced by chronic morphine injections, we used 0.6 M Ro 25-6981, a highly specific NR2B-containing NMDAR antagonist (39), as well as a low concentration of AP5 (5 M), which preferentially blocks NR2A-containing NMDARs at this level (40). At 0.1 M, Ro 25-6981 blocks ϳ90% of NR2B-mediated NMDA currents (39).…”

Casein Kinase II RegulatesN-Methyl-d-Aspartate Receptor Activity in Spinal Cords and Pain Hypersensitivity Induced by Nerve Injury

“…We used 0.6 mM Ro 25-6981 [(aR,bS)-a-(4-hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate], a highly specific GluN2B-containing NMDAR antagonist (Fischer et al, 1997;Zhao et al, 2012), as well as a low concentration of AP5 (5 mM), which preferentially blocks GluN2A-containing NMDARs at this concentration (Kimura and Matsuki, 2008;Zhao et al, 2012). In lamina II neurons from sham (n 5 11 neurons) and SNL (n 5 12 neurons) rats, Ro 25-6981 caused a similar reduction in the amplitude of NMDAR-EPSCs (Fig.…”

“…The average NMDAR-mediated mEPSCs were obtained after subtracting the average AMPAR-mediated mEPSCs from the average NMDARand AMPAR-mediated mixed mEPSCs. Because the NMDAR component of mEPSCs has a small amplitude and slow decay kinetic (Kimura and Matsuki, 2008), using the amplitude of NMDAR-mEPSCs would not be accurate to reflect the synaptic NMDAR activity. For this reason, we used the area under the curve to compare the changes in NMDARmediated mEPSCs.…”