title: Modification of STIM1 by O-linked N-acetylglucosamine (O-GlcNAc) attenuates store-operated calcium entry in neonatal cardiomyocytes.
abstract: Store-operated calcium entry (SOCE) is a major Ca(2+) signaling pathway responsible for regulating numerous transcriptional events. In cardiomyocytes SOCE has been shown to play an important role in regulating hypertrophic signaling pathways, including nuclear translocation of NFAT. Acute activation of pathways leading to O-GlcNAc synthesis have been shown to impair SOCE-mediated transcription and in diabetes, where O-GlcNAc levels are chronically elevated, cardiac hypertrophic signaling is also impaired. Therefore the goal of this study was to determine whether changes in cardiomyocyte O-GlcNAc levels impaired the function of STIM1, a widely recognized mediator of SOCE. We demonstrated that acute activation of SOCE in neonatal cardiomyocytes resulted in STIM1 puncta formation, which was inhibited in a dose-dependent manner by increasing O-GlcNAc synthesis with glucosamine or inhibiting O-GlcNAcase with thiamet-G. Glucosamine and thiamet-G also inhibited SOCE and were associated with increased O-GlcNAc modification of STIM1. These results suggest that activation of cardiomyocyte O-GlcNAcylation attenuates SOCE via STIM1 O-GlcNAcylation and that this may represent a new mechanism by which increased O-GlcNAc levels regulate Ca(2+)-mediated events in cardiomyocytes. Further, since SOCE is a fundamental mechanism underlying Ca(2+) signaling in most cells and tissues, it is possible that STIM1 represents a nexus linking protein O-GlcNAcylation with Ca(2+)-mediated transcription.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Alabama 35294, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zhu-Mauldin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Marsh
authors.forename: Luyun
authors.initials: L
authors.lastname: Zou
authors.forename: Richard B
authors.initials: RB
authors.lastname: Marchase
authors.forename: John C
authors.initials: JC
authors.lastname: Chatham
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D032342:Muscle Cells / Q000166:cytology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D011714:Pyrans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; D011714:Pyrans; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D013844:Thiazoles; C572247:thiamet G; D002118:Calcium; D000117:Acetylglucosamine