CaMKII versus DAPK1 Binding to GluN2B in Ischemic Neuronal Cell Death after Resuscitation from Cardiac Arrest
Olivia R. Buonarati,
Sarah G. Cook,
Dayton J. Goodell,
Nicholas E. Chalmers,
Nicole L. Rumian,
Jonathan E. Tullis,
Susana Restrepo,
Steven J. Coultrap,
Nidia Quillinan,
Paco S. Herson,
K. Ulrich Bayer
Affiliations
Olivia R. Buonarati
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Sarah G. Cook
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Dayton J. Goodell
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Nicholas E. Chalmers
Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Nicole L. Rumian
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Jonathan E. Tullis
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Susana Restrepo
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Steven J. Coultrap
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Nidia Quillinan
Program in Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Paco S. Herson
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
K. Ulrich Bayer
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Summary: DAPK1 binding to GluN2B was prominently reported to mediate ischemic cell death in vivo. DAPK1 and CaMKII bind to the same GluN2B region, and their binding is mutually exclusive. Here, we show that mutating the binding region on GluN2B (L1298A/R1300Q) protected against neuronal cell death induced by cardiac arrest followed by resuscitation. Importantly, the GluN2B mutation selectively abolished only CaMKII, but not DAPK1, binding. During ischemic or excitotoxic insults, CaMKII further accumulated at excitatory synapses, and this accumulation was mediated by GluN2B binding. Interestingly, extra-synaptic GluN2B decreased after ischemia, but its relative association with DAPK1 increased. Thus, ischemic neuronal death requires CaMKII binding to synaptic GluN2B, whereas any potential role for DAPK1 binding is restricted to a different, likely extra-synaptic population of GluN2B. : Ischemic insults cause excitotoxic neuronal cell death via NMDA receptor overstimulation. Buonarati et al. find that excitotoxic insults cause DAPK1 movement to extra-synaptic NMDA receptors and CaMKII movement to synaptic NMDA receptors; importantly, preventing this CaMKII movement protects neurons from ischemic death. Keywords: CaMKII, DAPK1, GluN2B, ischemia, cardiac arrest, cardiopulmonary resuscitation, excitotoxicity, hippocampus
