Limits...
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.).

Show MeSH

Related in: MedlinePlus

β‐adrenergic stimulation speeds twitch duration and restores entrained rhythmicity in cardiomyocytes expressing relatively low Ca2+‐affinity long QT syndrome calmodulin (CaM) mutants. A, Stimulated twitch decay (1 Hz) at baseline and following 100 nmol/L ISO. *P<0.05. Ai, Regardless of exogenous CaM expression, the twitch decay rate was faster following ISO. Data from (A) replotted as cell‐by‐cell response to ISO.**P<0.001; ***P<10−4; n=10 or 11. B, Representative Ca2+ transient for D96V‐CaM expressing fetal ventricular myocyte. Left panel shows 1‐Hz stimulation to illustrate baseline 2:1 block. Right panel shows an example of partial restoration of entrainment of Ca2+ transient to field stimulation. With ISO, the 2:1 activity spontaneously reverts to 1:1 activity. n=10. C, Representative Ca2+ transient for D130G‐CaM expressing fetal ventricular myocyte. Left panel shows 0.5‐Hz stimulation to illustrate baseline alternans. Right panel shows an example of recovery of entrainment following ISO. n=10. ISO indicates isoproterenol, WT, wild type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4309107&req=5

fig09: β‐adrenergic stimulation speeds twitch duration and restores entrained rhythmicity in cardiomyocytes expressing relatively low Ca2+‐affinity long QT syndrome calmodulin (CaM) mutants. A, Stimulated twitch decay (1 Hz) at baseline and following 100 nmol/L ISO. *P<0.05. Ai, Regardless of exogenous CaM expression, the twitch decay rate was faster following ISO. Data from (A) replotted as cell‐by‐cell response to ISO.**P<0.001; ***P<10−4; n=10 or 11. B, Representative Ca2+ transient for D96V‐CaM expressing fetal ventricular myocyte. Left panel shows 1‐Hz stimulation to illustrate baseline 2:1 block. Right panel shows an example of partial restoration of entrainment of Ca2+ transient to field stimulation. With ISO, the 2:1 activity spontaneously reverts to 1:1 activity. n=10. C, Representative Ca2+ transient for D130G‐CaM expressing fetal ventricular myocyte. Left panel shows 0.5‐Hz stimulation to illustrate baseline alternans. Right panel shows an example of recovery of entrainment following ISO. n=10. ISO indicates isoproterenol, WT, 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)

β‐adrenergic stimulation speeds twitch duration and restores entrained rhythmicity in cardiomyocytes expressing relatively low Ca2+‐affinity long QT syndrome calmodulin (CaM) mutants. A, Stimulated twitch decay (1 Hz) at baseline and following 100 nmol/L ISO. *P<0.05. Ai, Regardless of exogenous CaM expression, the twitch decay rate was faster following ISO. Data from (A) replotted as cell‐by‐cell response to ISO.**P<0.001; ***P<10−4; n=10 or 11. B, Representative Ca2+ transient for D96V‐CaM expressing fetal ventricular myocyte. Left panel shows 1‐Hz stimulation to illustrate baseline 2:1 block. Right panel shows an example of partial restoration of entrainment of Ca2+ transient to field stimulation. With ISO, the 2:1 activity spontaneously reverts to 1:1 activity. n=10. C, Representative Ca2+ transient for D130G‐CaM expressing fetal ventricular myocyte. Left panel shows 0.5‐Hz stimulation to illustrate baseline alternans. Right panel shows an example of recovery of entrainment following ISO. n=10. ISO indicates isoproterenol, WT, wild type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig09: β‐adrenergic stimulation speeds twitch duration and restores entrained rhythmicity in cardiomyocytes expressing relatively low Ca2+‐affinity long QT syndrome calmodulin (CaM) mutants. A, Stimulated twitch decay (1 Hz) at baseline and following 100 nmol/L ISO. *P<0.05. Ai, Regardless of exogenous CaM expression, the twitch decay rate was faster following ISO. Data from (A) replotted as cell‐by‐cell response to ISO.**P<0.001; ***P<10−4; n=10 or 11. B, Representative Ca2+ transient for D96V‐CaM expressing fetal ventricular myocyte. Left panel shows 1‐Hz stimulation to illustrate baseline 2:1 block. Right panel shows an example of partial restoration of entrainment of Ca2+ transient to field stimulation. With ISO, the 2:1 activity spontaneously reverts to 1:1 activity. n=10. C, Representative Ca2+ transient for D130G‐CaM expressing fetal ventricular myocyte. Left panel shows 0.5‐Hz stimulation to illustrate baseline alternans. Right panel shows an example of recovery of entrainment following ISO. n=10. ISO indicates isoproterenol, WT, 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