Sarcoplasmic reticulum calcium leak and cardiac arrhythmias
- PMID: 17956253
- DOI: 10.1042/BST0350952
Sarcoplasmic reticulum calcium leak and cardiac arrhythmias
Abstract
Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca(2+)) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca(2+) leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca(2+) leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca(2+) leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca(2+) leak through SR Ca(2+) release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.
Similar articles
-
Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure.Circ Res. 2005 Dec 9;97(12):1314-22. doi: 10.1161/01.RES.0000194329.41863.89. Epub 2005 Nov 3. Circ Res. 2005. PMID: 16269653
-
Calstabin deficiency, ryanodine receptors, and sudden cardiac death.Biochem Biophys Res Commun. 2004 Oct 1;322(4):1267-79. doi: 10.1016/j.bbrc.2004.08.032. Biochem Biophys Res Commun. 2004. PMID: 15336974 Review.
-
Defective cardiac ryanodine receptor regulation during atrial fibrillation.Circulation. 2005 Apr 26;111(16):2025-32. doi: 10.1161/01.CIR.0000162461.67140.4C. Circulation. 2005. PMID: 15851612
-
Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction.Biochem Soc Trans. 2007 Nov;35(Pt 5):946-51. doi: 10.1042/BST0350946. Biochem Soc Trans. 2007. PMID: 17956252 Review.
-
Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology.Circulation. 2013 Aug 27;128(9):970-81. doi: 10.1161/CIRCULATIONAHA.113.001746. Epub 2013 Jul 19. Circulation. 2013. PMID: 23877259
Cited by
-
Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions.Cell Death Discov. 2023 Jul 21;9(1):256. doi: 10.1038/s41420-023-01553-4. Cell Death Discov. 2023. PMID: 37479697 Free PMC article. Review.
-
The role of subunit cooperativity on ryanodine receptor 2 calcium signaling.Biophys J. 2023 Jan 3;122(1):215-229. doi: 10.1016/j.bpj.2022.11.008. Epub 2022 Nov 7. Biophys J. 2023. PMID: 36348625 Free PMC article.
-
Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling.J Mol Cell Cardiol. 2022 Sep;170:34-46. doi: 10.1016/j.yjmcc.2022.05.009. Epub 2022 Jun 2. J Mol Cell Cardiol. 2022. PMID: 35661621 Free PMC article.
-
Sacubitril/valsartan versus angiotensin inhibitors and arrhythmia endpoints in heart failure with reduced ejection fraction.Heart Rhythm O2. 2021 Dec 17;2(6Part B):724-732. doi: 10.1016/j.hroo.2021.09.009. eCollection 2021 Dec. Heart Rhythm O2. 2021. PMID: 34988523 Free PMC article.
-
Size Matters: Ryanodine Receptor Cluster Size Heterogeneity Potentiates Calcium Waves.Biophys J. 2019 Feb 5;116(3):530-539. doi: 10.1016/j.bpj.2018.12.017. Epub 2019 Jan 3. Biophys J. 2019. PMID: 30686487 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous