title: Nitric oxide induces Ca2+-independent activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII).
abstract: Both signaling by nitric oxide (NO) and by the Ca(2+)/calmodulin (CaM)-dependent protein kinase II α isoform (CaMKIIα) are implicated in two opposing forms of synaptic plasticity underlying learning and memory, as well as in excitotoxic/ischemic neuronal cell death. For CaMKIIα, these functions specifically involve also Ca(2+)-independent autonomous activity, traditionally generated by Thr-286 autophosphorylation. Here, we demonstrate that NO-induced S-nitrosylation of CaMKIIα also directly generated autonomous activity, and that CaMKII inhibition protected from NO-induced neuronal cell death. NO induced S-nitrosylation at Cys-280/289, and mutation of either site abolished autonomy, indicating that simultaneous nitrosylation at both sites was required. Additionally, autonomy was generated only when Ca(2+)/CaM was present during NO exposure. Thus, generation of this form of CaMKIIα autonomy requires simultaneous signaling by NO and Ca(2+). Nitrosylation also significantly reduced subsequent CaMKIIα autophosphorylation specifically at Thr-286, but not at Thr-305. A previously described reduction of CaMKII activity by S-nitrosylation at Cys-6 was also observed here, but only after prolonged (>5 min) exposure to NO donors. These results demonstrate a novel regulation of CaMKII by another second messenger system and indicate its involvement in excitotoxic neuronal cell death.
authors.affiliation: From the Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado 80045 steve.coultrap@ucdenver.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Coultrap
authors.affiliation: From the Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado 80045 ulli.bayer@ucdenver.edu.
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
mesh_terms: D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Autonomy; Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII); Calmodulin (CaM); Excitotoxicity; Kinase Regulation; Nitric Oxide; S-Nitrosylation