Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.
CA1 pyramidal neurons degenerate after transient forebrain ischemia, whereas neurons in other regions of the hippocampus remain intact. Here we show that in rat hippocampal CA1 neurons, forebrain ischemia induces the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit at Ser1232 (phospho-Ser1232). Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5). Inhibiting endogenous Cdk5, or perturbing interactions between Cdk5 and NR2A subunits, abolished NR2A phosphorylation at Ser1232 and protected CA1 pyramidal neurons from ischemic insult. Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons.
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017966:Pyramidal Cells / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D012694:Serine / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases