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Mentor: Johannes W. Hell, PhD
Year Entered Into Program: 2001
PhD Institution: University of Iowa, 2009 (M.D / Ph.D)
The post-synaptic density (PSD), a thickened area of the post-synaptic membrane visible under electron microscope, contains scaffolding proteins that cluster glutamate receptors at the synapse. N-methyl-D-aspartate (NMDA) receptors are concentrated along with a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors within the PSD. Ca2+ influx through the NMDA receptor plays a central role in mediating cellular changes leading to increased synaptic strength. Ca2+ influx through the NMDA receptor following excessive glutamate release is also thought to underlie many of the detrimental signaling cascades leading to cell death following cerebral ischemia. Ca2+/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine kinase, is important in mediating cellular responses to Ca2+ including changes subsequent to both LTP and ischemia. Activity-dependent subcellular localization of CaMKII within the PSD is mediated through its binding to the NMDA receptor. CaMKII strongly binds to two subunits, NR1 and NR2B. Two regions within the C-terminal cytosolic domain of NR2B, residues 839-1120 (NR2B-P) and residues 1290-1309 (NR2B-C), bind CaMKII. Autophosphorylation of CaMKII is required for binding at NR2B-P, whereas the presence of Ca2+/calmodulin is sufficient to induce CaMKII binding at NR2B-C. The C-terminal cytosolic portion of NR1 contains 4 regions, C0, C1, C2 and C2’ that are differentially present in 4 isoforms. Autophosphorylated CaMKII binds to the 30 residue-long, membrane-proximal, C0 region of NR1. The binding domain for CaMKII is located at the C-terminal end of the region and covers residues 847-858 where it competes for binding with Ca2+/calmodulin and a-actinin-2. Functional roles for CaMKII binding to the NMDA receptor could include targeting of CaMKII to the PSD, regulation of NMDA receptor activity, targeting of CaMKII to substrates for phosphorylation, and structural modification of the PSD. The goal of my research is to further clarify the functional significance of CaMKII binding to the NMDA receptor. My research utilizes knock-in mice with mutations in the CaMKII binding domains on NR1 and NR2B.
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