Letter | Published:

Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation

Nature volume 502, pages 372376 (17 October 2013) | Download Citation

Abstract

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca2+ handling and gene transcription1. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart2 and neurodegenerative diseases3,4. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca2+ concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias1. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.

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Acknowledgements

We thank Y. Hayashi for providing initial Camui samples, H. Schulman for helpful discussions, K. Margulies for human heart samples, L.-W. Jin, M. Melara and the University of California, Davis Alzheimer’s Disease Center (NIH-P30AG010129) for human brain samples, and J. H. Brown for providing CaMKIIδ-knockout mice. We thank Pfizer, Inc. for the gift of a breeding pair of HIP rats to F.D. This work was supported by American Heart Association 13SDG14680072 and National Institutes of Health (NIH) T32HL86350 (J.R.E.); NIH 1R01HL118474-01A1, NSF CBET 1133339, ADA 1-13-IN-70 and AHA 13GRNT16470034 (F.D.); NIH R01DK61671 and P01HL107153 (G.W.H.); NIH R01HL111600 (C.M.R.); NIH P01HL080101, R37HL30077 and Fondation Leducq Transatlantic CaMKII Alliance (D.M.B.). G.W.H. receives a share of royalty on sales of the CTD 110.6 antibody, which are managed by Johns Hopkins University.

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Affiliations

  1. Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, Davis, California 95616, USA

    • Jeffrey R. Erickson
    • , Laetitia Pereira
    • , Lianguo Wang
    • , Amanda Ferguson
    • , Khanha Dao
    • , Florin Despa
    • , Crystal M. Ripplinger
    •  & Donald M. Bers
  2. Department of Physiology, University of Otago, Dunedin 9054, New Zealand

    • Jeffrey R. Erickson
  3. Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA

    • Guanghui Han
    • , Ronald J. Copeland
    •  & Gerald W. Hart
  4. Department of Molecular and Biomedical Pharmacology, University of Kentucky, 900 S. Limestone, Lexington, Kentucky 40536, USA

    • Florin Despa

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Contributions

J.R.E. and D.M.B. conceived the project. J.R.E. and L.P. carried out most of the experiments. L.W. and C.M.R. conducted optical mapping and in vivo ECG experiments and analysis. G.H., R.J.C. and G.W.H. conducted ETD-MS analysis. A.F. and K.D. generated constructs, performed animal surgeries, and participated in data analysis. F.D. contributed diabetic rats and some analysis therewith. J.R.E. and D.M.B. wrote the manuscript, with assistance from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Donald M. Bers.

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DOI

https://doi.org/10.1038/nature12537

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