| Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy. | |
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MedLine Citation:
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PMID: 20484118 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cardiac-type sarco(endo)plasmic reticulum Ca(2)-ATPase (SERCA2a) plays a major role in cardiac muscle contractility. Phospholamban (PLN) regulates the function of SERCA2a via its Ser(16)-phosphorylation. Since it has been proposed that the Ser/Thr residues on cytoplasmic and nuclear proteins are modified by O-linked N-acetylglucosamine (O-GlcNAc), we examined the effect of O-GlcNAcylation on PLN function in rat adult cardiomyocytes. Studies using enzymatic labeling and co-immunoprecipitation of wild type and a series of mutants of PLN showed that PLN was O-GlcNAcylated and Ser(16) of PLN might be the site for O-GlcNAcylation. In cardiomyocytes treated with O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), the O-GlcNAcylation was significantly increased compared to non-treated cells. Simultaneously, Ser(16)-phosphorylation of PLN was reduced. In Chinese hamster ovary cells where PLN cDNA and O-GlcNAc transferase siRNA were co-transfected, the Ser(16)-phosphorylation of PLN was significantly increased compared to controls. The same results were observed in heart homogenates from diabetic rats. In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes. Unlike non-treated cells, the activity of SERCA2a and the profiles of calcium transients in PUGNAc-treated cardiomyocytes were not significantly changed even after treatment with catecholamine. These data suggest that PLN is O-GlcNAcylated to induce the inhibition of its phosphorylation, which correlates to the deterioration of cardiac function. This might define a novel mechanism by which PLN regulation of SERCA2a is altered under conditions where O-GlcNAcylation is increased, such as those occurring in diabetes. |
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Authors:
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Shunichi Yokoe; Michio Asahi; Toshihiro Takeda; Kinya Otsu; Naoyuki Taniguchi; Eiji Miyoshi; Keiichiro Suzuki |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-18 |
Journal Detail:
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Title: Glycobiology Volume: 20 ISSN: 1460-2423 ISO Abbreviation: Glycobiology Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-08 Completed Date: 2011-01-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9104124 Medline TA: Glycobiology Country: England |
Other Details:
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Languages: eng Pagination: 1217-26 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylglucosamine
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analogs & derivatives,
pharmacology Acylation Animals Blotting, Western CHO Cells Calcium / metabolism Calcium-Binding Proteins / genetics, metabolism* Catecholamines / pharmacology Cricetinae Cricetulus Cyclic AMP-Dependent Protein Kinases / metabolism Diabetes Mellitus, Experimental / complications*, metabolism, pathology Diabetic Cardiomyopathies / etiology*, metabolism, pathology Hela Cells Humans Immunoprecipitation Male Mutagenesis, Site-Directed Mutation Myocytes, Cardiac / cytology, drug effects, metabolism* N-Acetylglucosaminyltransferases / antagonists & inhibitors, genetics, metabolism* Oximes / pharmacology Phenylcarbamates / pharmacology Phosphorylation / drug effects Rats Rats, Sprague-Dawley Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism* beta-N-Acetylhexosaminidases / antagonists & inhibitors |
| Chemical | |
Reg. No./Substance:
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0/Calcium-Binding Proteins; 0/Catecholamines; 0/Oximes; 0/Phenylcarbamates; 0/phospholamban; 132489-69-1/N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; 7440-70-2/Calcium; 7512-17-6/Acetylglucosamine; EC 2.4.1.-/N-Acetylglucosaminyltransferases; EC 2.4.1.-/O-GlcNAc transferase; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.2.1.52/beta-N-Acetylhexosaminidases; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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