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

Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia.

Background: Congenital long-QT syndrome (LQTS) may present during fetal development and can be life-threatening. The molecular mechanism for the unusual early onset of LQTS during fetal development is unknown.

Objective: We sought to elucidate the molecular basis for severe fetal LQTS presenting at 19 weeks' gestation, the earliest known presentation of this disease.

Endothelial cells stimulate T cell NFAT nuclear translocation in the presence of cyclosporin A: involvement of the wnt/glycogen synthase kinase-3 beta pathway.

T cells resistant to the immunosuppressive drug cyclosporin A (CsA) may be important mediators of chronic graft rejection. We previously reported that T cells activated in the presence of endothelial cells (EC) develop resistance to CsA, and initiate IL-2 secretion within 8-12 h of triggering. CsA normally blocks the phosphatase, calcineurin, thus preventing nuclear translocation of the transcription factor, NFAT.