Journal article
Modification of STIM1 by O-linked N-Acetylglucosamine (O-GlcNAc) Attenuates Store-operated Calcium Entry in Neonatal Cardiomyocytes
The Journal of biological chemistry, Vol.287(46), pp.39094-39106
11/09/2012
Handle:
https://hdl.handle.net/2376/109016
PMCID: PMC3493950
PMID: 22992728
Abstract
Background:
Increased cellular
O
-GlcNAc levels decrease store-operated Ca
2+
entry (SOCE), however, the mechanism is not understood. STIM1 regulates SOCE, but effect of
O
-GlcNAc on STIM1 function is not known.
Results:
Increased cardiomyocyte
O
-GlcNAcylation attenuated STIM1 puncta formation, SOCE and increased
O
-GlcNAc modification of STIM1.
Conclusion:
O
-GlcNAc modification of STIM1 plays a key role in regulating SOCE.
Significance:
Protein
O
-GlcNAcylation regulates SOCE, a central Ca
2+
signaling pathway.
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.
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Details
- Title
- Modification of STIM1 by O-linked N-Acetylglucosamine (O-GlcNAc) Attenuates Store-operated Calcium Entry in Neonatal Cardiomyocytes
- Creators
- Xiaoyuan Zhu-Mauldin - From theSusan A Marsh - theLuyun Zou - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Alabama 35294 andRichard B Marchase - From theJohn C Chatham - From the
- Publication Details
- The Journal of biological chemistry, Vol.287(46), pp.39094-39106
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- HL104549; HL101192; HL110366 / National Institutes of Health
- Identifiers
- 99900547104301842
- Language
- English
- Resource Type
- Journal article