Key result
LQTS-associated Calmodulin mutations impaired Ca2+-dependent inactivation of L-type Ca2+ current and led to loss of Ca2+-transient entrainment, without affecting L-type Na current.
LQTS-associated CaM mutations disrupt intracellular Ca2+ regulation by impairing Ca2+-dependent inactivation of L-type Ca2+ current, a mechanism distinct from CPVT-associated mutations.
Findings in animal models should not alter LQTS care; leaves open human translation of CaM-Ca2+ mechanisms.
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.
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Hassan et al. (2014) studied Congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Calmodulin (CaM) mutations vs. Wild-type CaM was evaluated on Ca2+-dependent inactivation of L-type Ca2+ current and L-type Na current. LQTS-associated Calmodulin mutations impaired Ca2+-dependent inactivation of L-type Ca2+ current and led to loss of Ca2+-transient entrainment, without affecting L-type Na current.
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