A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation

Calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA-/- mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis.

[1]  B. Kobilka,et al.  Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. , 2003, The Journal of clinical investigation.

[2]  Mark E. Anderson,et al.  L-type Ca2+ channel facilitation mediated by phosphorylation of the beta subunit by CaMKII. , 2006, Molecular cell.

[3]  S. Holland,et al.  And Ulf Landmesser Remodeling/dysfunction and Survival after Myocardial Infarction for Left Ventricular Phox Critical Role of the Nad(p)h Oxidase Subunit P47 , 2007 .

[4]  Karl Swedberg,et al.  Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. , 2003, The New England journal of medicine.

[5]  M. Kennedy,et al.  Activation of type II calcium/calmodulin-dependent protein kinase by Ca2+/calmodulin is inhibited by autophosphorylation of threonine within the calmodulin-binding domain. , 1990, The Journal of biological chemistry.

[6]  Yuejin Wu,et al.  Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy , 2006, Circulation.

[7]  Vadim N. Gladyshev,et al.  Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Dan M Roden,et al.  Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants: Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes , 2007, Circulation.

[9]  Guy Salama,et al.  Calmodulin kinase II inhibition protects against structural heart disease , 2005, Nature Medicine.

[10]  S. Young,et al.  Calcific Aortic Valve Stenosis in Old Hypercholesterolemic Mice , 2006, Circulation.

[11]  J. H. Schwartz,et al.  Phosphorylation-dependent subcellular translocation of a Ca2+/calmodulin-dependent protein kinase produces an autonomous enzyme in Aplysia neurons , 1985, The Journal of cell biology.

[12]  A. Zhabotinsky.  Bistability in the Ca(2+)/calmodulin-dependent protein kinase-phosphatase system. , 2000, Biophysical journal.

[13]  H. Schulman,et al.  Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase by autophosphorylation: ATP modulates production of an autonomous enzyme. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Hiroyuki Tsutsui,et al.  Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice: Role of Oxidative Stress , 2000, Circulation research.

[15]  A. Caudy,et al.  Role for a bidentate ribonuclease in the initiation step of RNA interference , 2001 .

[16]  R. Colbran,et al.  Inactivation of Ca2+/calmodulin-dependent protein kinase II by basal autophosphorylation. , 1993, The Journal of biological chemistry.

[17]  E. Olson,et al.  CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. , 2006, The Journal of clinical investigation.

[18]  C A Beltrami,et al.  Apoptosis in the failing human heart. , 1997, The New England journal of medicine.

[19]  古塚 大介,et al.  ペンチレンテトラゾール誘発痙攣によるマウス脳Ca^ /calmodulin dependent protein kinase II活性の変化 , 1996 .

[20]  Angus C. Nairn,et al.  Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme , 2005, Cell.

[21]  J. Engelhardt,et al.  Requirement for Rac1-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain , 2004, Circulation research.

[22]  M. Cuénod,et al.  Screening of Thiol Compounds: Depolarization‐Induced Release of Glutathione and Cysteine from Rat Brain Slices , 1992, Journal of neurochemistry.

[23]  N. Brot,et al.  High-quality life extension by the enzyme peptide methionine sulfoxide reductase , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  H. Schulman,et al.  Calmodulin Trapping by Calcium-Calmodulin-Dependent Protein Kinase , 1992, Science.

[25]  Mark E. Anderson,et al.  RETRACTED: L-Type Ca2+ Channel Facilitation Mediated by Phosphorylation of the β Subunit by CaMKII , 2006 .

[26]  D. Matthews,et al.  Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β , 2006, Proceedings of the National Academy of Sciences.

[27]  Fach,et al.  Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) , 1999, The Lancet.

[28]  E. Stadtman,et al.  Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Eren,et al.  Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo. , 2006, American journal of physiology. Heart and circulatory physiology.

[30]  S. Heinemann,et al.  Regulation of cell function by methionine oxidation and reduction , 2001, The Journal of physiology.

[31]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[32]  F. Abboud,et al.  Mechanical stimulation increases intracellular calcium concentration in nodose sensory neurons , 1995, Neuroscience.

[33]  J. Yates,et al.  A model for random sampling and estimation of relative protein abundance in shotgun proteomics. , 2004, Analytical chemistry.

[34]  J. Keaney,et al.  Are ACE inhibitors a "magic bullet" against oxidative stress? , 2001, Circulation.

[35]  P. Greengard,et al.  Ca2+-dependent protein phosphorylation system in membranes from various tissues, and its activation by "calcium-dependent regulator". , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Barford.  The role of cysteine residues as redox-sensitive regulatory switches. , 2004, Current opinion in structural biology.

[37]  D. Bers.  Beyond beta blockers , 2005, Nature Medicine.

[38]  M. Crow,et al.  Activation of CaMKIIδC Is a Common Intermediate of Diverse Death Stimuli-induced Heart Muscle Cell Apoptosis* , 2007, Journal of Biological Chemistry.

[39]  D. Templeton,et al.  Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain. , 2004, The Biochemical journal.

[40]  R. Bernards,et al.  A System for Stable Expression of Short Interfering RNAs in Mammalian Cells , 2002, Science.

[41]  K. Griendling,et al.  Modulation of vascular smooth muscle signaling by reactive oxygen species. , 2006, Physiology.

[42]  M. Jessup,et al.  Heart failure. , 2003, The New England journal of medicine.

[43]  Maristela L Onozato,et al.  Angiotensin II and Oxidative Stress in Dahl Salt-Sensitive Rat With Heart Failure , 2002, Hypertension.

[44]  J. Hare.  Oxidative stress and apoptosis in heart failure progression. , 2001, Circulation research.

[45]  B. Matthews,et al.  Peptide methionine sulfoxide reductase: structure, mechanism of action, and biological function. , 2002, Archives of biochemistry and biophysics.

[46]  N. Tonks,et al.  Protein tyrosine phosphatases: from genes, to function, to disease , 2006, Nature Reviews Molecular Cell Biology.

[47]  S. Heinemann,et al.  Three methionine residues located within the regulator of conductance for K+ (RCK) domains confer oxidative sensitivity to large‐conductance Ca2+‐activated K+ channels , 2006, The Journal of physiology.

[48]  L. Klotz,et al.  Rac upregulates tissue inhibitor of metalloproteinase‐1 expression by redox‐dependent activation of extracellular signal‐regulated kinase signaling , 2006, The FEBS journal.

[49]  Andy Hudmon,et al.  Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. , 2002, The Biochemical journal.

[50]  J. McCubrey,et al.  Redox Regulation of the Calcium/Calmodulin-dependent Protein Kinases* , 2004, Journal of Biological Chemistry.

[51]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[52]  Dan M Roden,et al.  Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy , 2002, Circulation.