Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms.
J Am Heart Assoc
; 3(3): e000996, 2014 Jun 23.
Article
en En
| MEDLINE
| ID: mdl-24958779
ABSTRACT
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 ANDRESULTS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arritmias Cardíacas
/
Calmodulina
/
Calcio
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Miocitos Cardíacos
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Mutación
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Am Heart Assoc
Año:
2014
Tipo del documento:
Article