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

Yin G, Hassan F, Haroun AR, Murphy LL, Crotti L, Schwartz PJ, George AL, Satin J - J Am Heart Assoc (2014)

Bottom Line: 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 led to loss of Ca2+-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>CaM-F142L.CaM mutations associated with LQTS may not affect L-type Na+ current but may evoke defective Ca2+-dependent inactivation of L-type Ca2+ current.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY (G.Y., F.H., A.R.H., J.S.).

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Peak current‐voltage relationships for ICa,L in fetal ventricular cardiomyocytes. WT calmodulin data are repeated in each panel for clarity of presentation. No significant differences were noted in voltage dependence or amplitude. See Table 3 for Boltzmann distribution fitted parameters. WT indicates wild type.
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fig03: Peak current‐voltage relationships for ICa,L in fetal ventricular cardiomyocytes. WT calmodulin data are repeated in each panel for clarity of presentation. No significant differences were noted in voltage dependence or amplitude. See Table 3 for Boltzmann distribution fitted parameters. WT indicates wild type.

Mentions: We tested the hypothesis that LQTS‐CaM mutations with impaired C‐domain Ca2+ affinity will slow ICa,L decay in a native cardiomyocyte environment due to impaired CDI.7Figure 2A illustrates representative current sweeps normalized to peak current for FVM expressing exogenous WT CaM superimposed on traces from cells expressing each of the LQTS‐CaM mutants. All LQTS‐CaM mutants slow ICa,L decay with the 2 relatively low Ca2+ Kd CaM‐mutants with altered highly conserved aspartic acids that directly chelate the Ca2+ ion, showing relatively greater effect2 (Figure 2). Current density and voltage dependence of current activation were not different between FVM expressing WT or LQTS‐CaM mutants (Figure 3; Table 3). In contrast, the CPVT‐association CaM mutation N54I did not significantly affect CDI (Figure 4). These data suggest that attenuated CDI and resulting slower ICa,L decay can contribute to mutant CaM‐associated LQTS but not CPVT.


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

Yin G, Hassan F, Haroun AR, Murphy LL, Crotti L, Schwartz PJ, George AL, Satin J - J Am Heart Assoc (2014)

Peak current‐voltage relationships for ICa,L in fetal ventricular cardiomyocytes. WT calmodulin data are repeated in each panel for clarity of presentation. No significant differences were noted in voltage dependence or amplitude. See Table 3 for Boltzmann distribution fitted parameters. WT indicates wild type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309107&req=5

fig03: Peak current‐voltage relationships for ICa,L in fetal ventricular cardiomyocytes. WT calmodulin data are repeated in each panel for clarity of presentation. No significant differences were noted in voltage dependence or amplitude. See Table 3 for Boltzmann distribution fitted parameters. WT indicates wild type.
Mentions: We tested the hypothesis that LQTS‐CaM mutations with impaired C‐domain Ca2+ affinity will slow ICa,L decay in a native cardiomyocyte environment due to impaired CDI.7Figure 2A illustrates representative current sweeps normalized to peak current for FVM expressing exogenous WT CaM superimposed on traces from cells expressing each of the LQTS‐CaM mutants. All LQTS‐CaM mutants slow ICa,L decay with the 2 relatively low Ca2+ Kd CaM‐mutants with altered highly conserved aspartic acids that directly chelate the Ca2+ ion, showing relatively greater effect2 (Figure 2). Current density and voltage dependence of current activation were not different between FVM expressing WT or LQTS‐CaM mutants (Figure 3; Table 3). In contrast, the CPVT‐association CaM mutation N54I did not significantly affect CDI (Figure 4). These data suggest that attenuated CDI and resulting slower ICa,L decay can contribute to mutant CaM‐associated LQTS but not CPVT.

Bottom Line: 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 led to loss of Ca2+-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>CaM-F142L.CaM mutations associated with LQTS may not affect L-type Na+ current but may evoke defective Ca2+-dependent inactivation of L-type Ca2+ current.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY (G.Y., F.H., A.R.H., J.S.).

Show MeSH
Related in: MedlinePlus