Publication Date:
2013-10-01
Description:
Ca(2+)/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, Ca(2+) handling and gene transcription. 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 heart and neurodegenerative diseases. 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 Ca(2+) 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 Ca(2+) release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIdelta. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801227/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801227/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erickson, Jeffrey R -- Pereira, Laetitia -- Wang, Lianguo -- Han, Guanghui -- Ferguson, Amanda -- Dao, Khanha -- Copeland, Ronald J -- Despa, Florin -- Hart, Gerald W -- Ripplinger, Crystal M -- Bers, Donald M -- 1R01HL118474-01A1/HL/NHLBI NIH HHS/ -- P01 HL080101/HL/NHLBI NIH HHS/ -- P01 HL107153/HL/NHLBI NIH HHS/ -- P01HL080101/HL/NHLBI NIH HHS/ -- P01HL107153/HL/NHLBI NIH HHS/ -- P30 AG010129/AG/NIA NIH HHS/ -- P30AG010129/AG/NIA NIH HHS/ -- R01 DK061671/DK/NIDDK NIH HHS/ -- R01 HL030077/HL/NHLBI NIH HHS/ -- R01 HL105242/HL/NHLBI NIH HHS/ -- R01 HL111600/HL/NHLBI NIH HHS/ -- R01 HL118474/HL/NHLBI NIH HHS/ -- R01DK61671/DK/NIDDK NIH HHS/ -- R01HL111600/HL/NHLBI NIH HHS/ -- R37 HL030077/HL/NHLBI NIH HHS/ -- R37HL30077/HL/NHLBI NIH HHS/ -- T32 HL086350/HL/NHLBI NIH HHS/ -- T32HL86350/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Oct 17;502(7471):372-6. doi: 10.1038/nature12537. Epub 2013 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of California, Davis, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24077098" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylglucosamine/metabolism
;
Animals
;
Arrhythmias, Cardiac/complications/enzymology/*metabolism
;
Benzylamines/pharmacology
;
Brain/drug effects/enzymology
;
Calcium/metabolism
;
Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
;
Diabetes Complications/enzymology/*metabolism
;
Diazooxonorleucine/pharmacology
;
Enzyme Activation/drug effects
;
Glucose/metabolism/pharmacology
;
Glycosylation/drug effects
;
Humans
;
Hyperglycemia/complications/enzymology/*metabolism
;
Mice
;
Myocardium/cytology/enzymology
;
Myocytes, Cardiac/enzymology/metabolism
;
Rats
;
Sarcoplasmic Reticulum/metabolism
;
Sulfonamides/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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