Abstract
Calcium (Ca2+) ions are a key second messenger involved in the rhythmic excitation and contraction of cardiomyocytes throughout the heart. Proper function of Ca2+-handling proteins is required for healthy cardiac function, whereas disruption in any of these can cause cardiac arrhythmias. This comprehensive review provides a broad overview of the roles of Ca2+-handling proteins and their regulators in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. Major Ca2+ channels and Ca2+-sensitive regulatory proteins involved in cardiac excitation–contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, short QT syndrome, and arrhythmogenic right-ventricular cardiomyopathy are discussed with particular emphasis on subtypes caused by mutations in Ca2+-handling proteins.
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Abbreviations
- AF:
-
Atrial fibrillation
- APD:
-
Action potential duration
- Ca2+ :
-
Calcium ion
- CRU:
-
Calcium release unit
- CaMKII:
-
Calcium/calmodulin-dependent protein kinase II
- CICR:
-
Calcium-induced calcium release
- CPVT:
-
Catecholaminergic polymorphic ventricular tachycardia
- DAD:
-
Delayed after-depolarization
- EAD:
-
Early after-depolarization
- ECG:
-
Electrocardiogram
- EC:
-
Excitation–contraction
- FKBP 12.6:
-
FK-506-binding protein 12.6
- K+ :
-
Potassium ion
- LQTS:
-
Long QT syndrome
- LTCC:
-
Voltage-gated L-type calcium channel
- Na+ :
-
Sodium ion
- NCX:
-
Sodium-calcium exchanger
- PKA:
-
Protein kinase A
- PLN:
-
Phospholamban
- PP:
-
Protein phosphatase
- RyR2:
-
Ryanodine receptor type-2
- SERCA2a:
-
Sarco/endoplasmic reticulum Ca2+-ATPase-2a
- SPEG:
-
Striated preferentially expressed protein kinase
- SR:
-
Sarcoplasmic reticulum
- SOICR:
-
Store overload-induced calcium release
- VT:
-
Ventricular tachycardia
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This work was supported by National Institutes of Health grants R01-HL147108, R01-HL153350, and R01-HL089598 (to X.H.T.W.), the Robert and Janice McNair Foundation McNair MD/PhD Scholars Program (J.K.), and the Baylor College of Medicine Medical Scientist Training Program (T32-GM136611; J.K., O.M., K.H.).
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Keefe, J.A., Moore, O.M., Ho, K.S. et al. Role of Ca2+ in healthy and pathologic cardiac function: from normal excitation–contraction coupling to mutations that cause inherited arrhythmia. Arch Toxicol 97, 73–92 (2023). https://doi.org/10.1007/s00204-022-03385-0
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DOI: https://doi.org/10.1007/s00204-022-03385-0