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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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Loss of Ca2+ transient entrainment is dominated by faulty reuptake in myocytes expressing the lowest Ca2+‐affinity calmodulin (CaM) mutants. A, Representative Ca2+ transients for 1‐Hz stimulation frequency. WT CaM and F142L‐CaM expressing cardiomyocyte Ca2+ transients were entrained to 1‐Hz stimuli. Pathological loss of entrainment categorized as overload (middle and lower left for D96V‐CaM and D130G, respectively), reuptake defective (middle right for D130G‐CaM), and alternans (lower right). The lower left D130G trace displaying overload (blue) is at a level greater than the WT diastolic level (upper left panel). Note that the representative alternans trace (lower right, red) is displaced by 1 fluorescent unit to illustrate an alternating pattern of relatively large‐ and small‐amplitude transients. B, Summary of pathological Ca2+‐transient phenotypes. For statistical testing, we tested the hypothesis that long QT syndromeh CaM mutants induced any pathological phenotype. N=20 cells for each group; P<10−4. WT indicates wild type.
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fig06: Loss of Ca2+ transient entrainment is dominated by faulty reuptake in myocytes expressing the lowest Ca2+‐affinity calmodulin (CaM) mutants. A, Representative Ca2+ transients for 1‐Hz stimulation frequency. WT CaM and F142L‐CaM expressing cardiomyocyte Ca2+ transients were entrained to 1‐Hz stimuli. Pathological loss of entrainment categorized as overload (middle and lower left for D96V‐CaM and D130G, respectively), reuptake defective (middle right for D130G‐CaM), and alternans (lower right). The lower left D130G trace displaying overload (blue) is at a level greater than the WT diastolic level (upper left panel). Note that the representative alternans trace (lower right, red) is displaced by 1 fluorescent unit to illustrate an alternating pattern of relatively large‐ and small‐amplitude transients. B, Summary of pathological Ca2+‐transient phenotypes. For statistical testing, we tested the hypothesis that long QT syndromeh CaM mutants induced any pathological phenotype. N=20 cells for each group; P<10−4. WT indicates wild type.

Mentions: Data were analyzed for Figures 5C, 6B, 7B, and 7D with the chi‐square test. Figure 9A was analyzed with 1‐way ANOVA with Dunn's multiple comparison test. Figure 9A and the remaining data analysis passed the D'Agostino and Pearson test and the Shapiro‐Wilk test for normality, and tests of statistical difference for the remaining data were performed using the t test with statistical significance correction of multiple comparisons and α=0.05 using the Holm‐Sidak method in GraphPad Prism version 6.0 for Windows (GraphPad Software, La Jolla, CA).


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)

Loss of Ca2+ transient entrainment is dominated by faulty reuptake in myocytes expressing the lowest Ca2+‐affinity calmodulin (CaM) mutants. A, Representative Ca2+ transients for 1‐Hz stimulation frequency. WT CaM and F142L‐CaM expressing cardiomyocyte Ca2+ transients were entrained to 1‐Hz stimuli. Pathological loss of entrainment categorized as overload (middle and lower left for D96V‐CaM and D130G, respectively), reuptake defective (middle right for D130G‐CaM), and alternans (lower right). The lower left D130G trace displaying overload (blue) is at a level greater than the WT diastolic level (upper left panel). Note that the representative alternans trace (lower right, red) is displaced by 1 fluorescent unit to illustrate an alternating pattern of relatively large‐ and small‐amplitude transients. B, Summary of pathological Ca2+‐transient phenotypes. For statistical testing, we tested the hypothesis that long QT syndromeh CaM mutants induced any pathological phenotype. N=20 cells for each group; P<10−4. WT indicates wild type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4309107&req=5

fig06: Loss of Ca2+ transient entrainment is dominated by faulty reuptake in myocytes expressing the lowest Ca2+‐affinity calmodulin (CaM) mutants. A, Representative Ca2+ transients for 1‐Hz stimulation frequency. WT CaM and F142L‐CaM expressing cardiomyocyte Ca2+ transients were entrained to 1‐Hz stimuli. Pathological loss of entrainment categorized as overload (middle and lower left for D96V‐CaM and D130G, respectively), reuptake defective (middle right for D130G‐CaM), and alternans (lower right). The lower left D130G trace displaying overload (blue) is at a level greater than the WT diastolic level (upper left panel). Note that the representative alternans trace (lower right, red) is displaced by 1 fluorescent unit to illustrate an alternating pattern of relatively large‐ and small‐amplitude transients. B, Summary of pathological Ca2+‐transient phenotypes. For statistical testing, we tested the hypothesis that long QT syndromeh CaM mutants induced any pathological phenotype. N=20 cells for each group; P<10−4. WT indicates wild type.
Mentions: Data were analyzed for Figures 5C, 6B, 7B, and 7D with the chi‐square test. Figure 9A was analyzed with 1‐way ANOVA with Dunn's multiple comparison test. Figure 9A and the remaining data analysis passed the D'Agostino and Pearson test and the Shapiro‐Wilk test for normality, and tests of statistical difference for the remaining data were performed using the t test with statistical significance correction of multiple comparisons and α=0.05 using the Holm‐Sidak method in GraphPad Prism version 6.0 for Windows (GraphPad Software, La Jolla, CA).

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