title: S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ.
abstract: NO is known to modulate calcium handling and cellular signaling in the myocardium, but key targets for NO in the heart remain unidentified. Recent reports have implied that NO can activate calcium/calmodulin (Ca(2+)/CaM)-dependent protein kinase II (CaMKII) in neurons and the heart. Here we use our novel sensor of CaMKII activation, Camui, to monitor changes in the conformation and activation of cardiac CaMKII (CaMKIIδ) activity after treatment with the NO donor S-nitrosoglutathione (GSNO). We demonstrate that exposure to NO after Ca(2+)/CaM binding to CaMKIIδ results in autonomous kinase activation, which is abolished by mutation of the Cys-290 site. However, exposure of CaMKIIδ to GSNO prior to Ca(2+)/CaM exposure strongly suppresses kinase activation and conformational change by Ca(2+)/CaM. This NO-induced inhibition was ablated by mutation of the Cys-273 site. We found parallel effects of GSNO on CaM/CaMKIIδ binding and CaMKIIδ-dependent ryanodine receptor activation in adult cardiac myocytes. We conclude that NO can play a dual role in regulating cardiac CaMKIIδ activity.
authors: From the Department of Physiology, University of Otago, Dunedin 9016, New Zealand and.
authors: Jeffrey R
authors: JR
authors: Erickson
authors: the Department of Pharmacology, University of California, Davis, CA 95616.
authors: C Blake
authors: CB
authors: Nichols
authors: the Department of Pharmacology, University of California, Davis, CA 95616.
authors: Hitoshi
authors: H
authors: Uchinoumi
authors: the Department of Pharmacology, University of California, Davis, CA 95616.
authors: Matthew L
authors: ML
authors: Stein
authors: the Department of Pharmacology, University of California, Davis, CA 95616.
authors: Julie
authors: J
authors: Bossuyt
authors: the Department of Pharmacology, University of California, Davis, CA 95616 dmbers@ucdavis.edu.
authors: Donald M
authors: DM
authors: Bers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009206:Myocardium / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
chemical_list: D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+/calmodulin-dependent protein kinase II (CaMKII); S-nitrosylation; nitric oxide; nitrosylation; protein kinase