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Yin, G.* ; Hassan, F.* ; Haroun, A.R.* ; Murphy, L.L.* ; Crotti, L. ; Schwartz, P.J.* ; George, A.L. Jr.* ; Satin, J.*

Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms.

J. Am. Heart Assoc. 3:e000996 (2014)
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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 Ca(2+) homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca(2+)-dependent inactivation of L-type Ca(2+) 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 Ca(2+)-dependent inactivation, whereas the CPVT-CaM mutant N54I had no effect on Ca(2+)-dependent inactivation. LQTS-CaM mutants led to loss of Ca(2+)-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>CaM-F142L. This rank order follows measured Ca(2+)-CaM affinities for wild-type and mutant CaM. Acute isoproterenol restored entrainment for CaM-130G and CaM-D96V but caused irreversible cytosolic Ca(2+) 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 Ca(2+)-dependent inactivation of L-type Ca(2+) current.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords L‐type Ca2+ Channel ; Calcium ; Calmodulin ; Cardiomyocyte ; Long Qt Syndrome
e-ISSN 2047-9980
Journal Journal of the American Heart Association
Quellenangaben Volume: 3, Issue: 3, Pages: , Article Number: e000996 Supplement: ,
Publisher Wiley
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)