BACKGROUND: Calmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia-susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS-associated CaM mutants disrupt Ca2+ homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca2+-dependent inactivation of L-type Ca2+ current. METHODS AND RESULTS: We coexpressed CaM mutants with the human cardiac Na channel (NaV1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS- and CPVT-associated CaM mutations (LQTS- and CPVT-CaM). LQTS-CaM mutants do not consistently affect L-type Na current in heterologous cells or native cardiomyocytes, suggesting that the Na channel does not contribute to LQTS pathogenesis in the context of CaM mutations. LQTS-CaM mutants (D96V, D130G, F142L) impaired Ca2+-dependent inactivation, whereas the CPVT-CaM mutant N54I had no effect on Ca2+-dependent inactivation. LQTS-CaM mutants led to loss of Ca2+-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>>CaM-F142L. This rank order follows measured Ca2+-CaM affinities for wild-type and mutant CaM. Acute isoproterenol restored entrainment for CaM-130G and CaM-D96V but caused irreversible cytosolic Ca2+ overload for cells expressing a CPVT-CaM mutant. CONCLUSIONS: CaM mutations associated with LQTS may not affect L-type Na+ current but may evoke defective Ca2+-dependent inactivation of L-type Ca2+ current
Yin, G., Hassan, F., Haroun, A., Murphy, L., Crotti, L., Schwartz, P., et al. (2014). Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms. JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE, 3(3), 1-14 [10.1161/JAHA.114.000996].
Citazione: | Yin, G., Hassan, F., Haroun, A., Murphy, L., Crotti, L., Schwartz, P., et al. (2014). Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms. JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE, 3(3), 1-14 [10.1161/JAHA.114.000996]. | |
Tipo: | Articolo in rivista - Articolo scientifico | |
Carattere della pubblicazione: | Scientifica | |
Presenza di un coautore afferente ad Istituzioni straniere: | Si | |
Titolo: | Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms | |
Autori: | Yin, G; Hassan, F; Haroun, A; Murphy, L; Crotti, L; Schwartz, P; George, A; Satin, J | |
Autori: | ||
Data di pubblicazione: | 2014 | |
Lingua: | English | |
Rivista: | JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1161/JAHA.114.000996 | |
Appare nelle tipologie: | 01 - Articolo su rivista |
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