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Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca(2+) channel.

Panáková D, Werdich AA, Macrae CA - Nature (2010)

Bottom Line: Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel.These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function.The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

View Article: PubMed Central - PubMed

Affiliation: Brigham and Women's Hospital/Harvard Medical School, Cardiovascular Division, 75 Francis Street, Thorn 11, Boston, Massachusetts 02115, USA.

ABSTRACT
Electrical gradients are critical for many biological processes, including the normal function of excitable tissues, left-right patterning, organogenesis and wound healing. The fundamental mechanisms that regulate the establishment and maintenance of such electrical polarities are poorly understood. Here we identify a gradient of electrical coupling across the developing ventricular myocardium using high-speed optical mapping of transmembrane potentials and calcium concentrations in the zebrafish heart. We excluded a role for differences in cellular excitability, connexin localization, tissue geometry and mechanical inputs, but in contrast we were able to demonstrate that non-canonical Wnt11 signals are required for the genesis of this myocardial electrical gradient. Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel. These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function. The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

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Wnt11 regulates Ca2+ transient amplitudes in cardiomyocytesa, Averaged Ca2+ transients from ROIs in b, c, e, f. A = amplitude and B = baseline.b, c, e, f, Colour maps of Ca2+ transient amplitudes from wildtype hearts (b), Wnt11 morphants (c), cacna1c (e) and cacna1c+thapsigargin+caffeine-treated embryos (f). Colour code depicts Ca2+ transient amplitudes in fluorescence ratio units (F340/F380). Squares indicate ROIs for measurements averaged in a and d.d, Mean Ca2+ transient amplitudes. One-way ANOVA, *p<0.05 for comparisons with wildtype. Error bars depict SEM.g, Isochronal map of cacna1c heart. The colour code depicts timing of activation. Squares indicate ROIs for conduction velocity estimation. Arrows display average velocity vector in each ROI. OC=outer curvature, IC=inner curvature.h, i, Mean estimated conduction velocities of cacna1c (h) and nifedipine-treated (i) hearts. Student's t-test, *p<0.05. Error bars depict SEM.All experiments were performed at 72hpf.
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Figure 3: Wnt11 regulates Ca2+ transient amplitudes in cardiomyocytesa, Averaged Ca2+ transients from ROIs in b, c, e, f. A = amplitude and B = baseline.b, c, e, f, Colour maps of Ca2+ transient amplitudes from wildtype hearts (b), Wnt11 morphants (c), cacna1c (e) and cacna1c+thapsigargin+caffeine-treated embryos (f). Colour code depicts Ca2+ transient amplitudes in fluorescence ratio units (F340/F380). Squares indicate ROIs for measurements averaged in a and d.d, Mean Ca2+ transient amplitudes. One-way ANOVA, *p<0.05 for comparisons with wildtype. Error bars depict SEM.g, Isochronal map of cacna1c heart. The colour code depicts timing of activation. Squares indicate ROIs for conduction velocity estimation. Arrows display average velocity vector in each ROI. OC=outer curvature, IC=inner curvature.h, i, Mean estimated conduction velocities of cacna1c (h) and nifedipine-treated (i) hearts. Student's t-test, *p<0.05. Error bars depict SEM.All experiments were performed at 72hpf.

Mentions: Ca2+ has been identified as an important second messenger in Wnt non-canonical signaling more than a decade ago25. Subsequent studies have revealed several distinct members of the Wnt/Ca2+ pathway22. However, the most proximal events of Wnt/Ca2+ signaling remain incompletely understood. In cardiomyocytes, intracellular Ca2+ concentrations ([Ca2+]i) change substantially within milliseconds during the excitation-contraction cycle, with baseline [Ca2+]i levels attained at diastole and maximum concentrations at systole (Fig. 3a). This phasic [Ca2+]i transient requires the orchestrated operation of multiple ion channels and transporters; including the L-type Ca2+ channel (LTCC), the major transmembrane Ca2+ conductance channel, and SERCA, the sarcoplasmic reticulum (SR) Ca2+ATP-ase, which actively transports Ca2+ into the SR26.


Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca(2+) channel.

Panáková D, Werdich AA, Macrae CA - Nature (2010)

Wnt11 regulates Ca2+ transient amplitudes in cardiomyocytesa, Averaged Ca2+ transients from ROIs in b, c, e, f. A = amplitude and B = baseline.b, c, e, f, Colour maps of Ca2+ transient amplitudes from wildtype hearts (b), Wnt11 morphants (c), cacna1c (e) and cacna1c+thapsigargin+caffeine-treated embryos (f). Colour code depicts Ca2+ transient amplitudes in fluorescence ratio units (F340/F380). Squares indicate ROIs for measurements averaged in a and d.d, Mean Ca2+ transient amplitudes. One-way ANOVA, *p<0.05 for comparisons with wildtype. Error bars depict SEM.g, Isochronal map of cacna1c heart. The colour code depicts timing of activation. Squares indicate ROIs for conduction velocity estimation. Arrows display average velocity vector in each ROI. OC=outer curvature, IC=inner curvature.h, i, Mean estimated conduction velocities of cacna1c (h) and nifedipine-treated (i) hearts. Student's t-test, *p<0.05. Error bars depict SEM.All experiments were performed at 72hpf.
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Figure 3: Wnt11 regulates Ca2+ transient amplitudes in cardiomyocytesa, Averaged Ca2+ transients from ROIs in b, c, e, f. A = amplitude and B = baseline.b, c, e, f, Colour maps of Ca2+ transient amplitudes from wildtype hearts (b), Wnt11 morphants (c), cacna1c (e) and cacna1c+thapsigargin+caffeine-treated embryos (f). Colour code depicts Ca2+ transient amplitudes in fluorescence ratio units (F340/F380). Squares indicate ROIs for measurements averaged in a and d.d, Mean Ca2+ transient amplitudes. One-way ANOVA, *p<0.05 for comparisons with wildtype. Error bars depict SEM.g, Isochronal map of cacna1c heart. The colour code depicts timing of activation. Squares indicate ROIs for conduction velocity estimation. Arrows display average velocity vector in each ROI. OC=outer curvature, IC=inner curvature.h, i, Mean estimated conduction velocities of cacna1c (h) and nifedipine-treated (i) hearts. Student's t-test, *p<0.05. Error bars depict SEM.All experiments were performed at 72hpf.
Mentions: Ca2+ has been identified as an important second messenger in Wnt non-canonical signaling more than a decade ago25. Subsequent studies have revealed several distinct members of the Wnt/Ca2+ pathway22. However, the most proximal events of Wnt/Ca2+ signaling remain incompletely understood. In cardiomyocytes, intracellular Ca2+ concentrations ([Ca2+]i) change substantially within milliseconds during the excitation-contraction cycle, with baseline [Ca2+]i levels attained at diastole and maximum concentrations at systole (Fig. 3a). This phasic [Ca2+]i transient requires the orchestrated operation of multiple ion channels and transporters; including the L-type Ca2+ channel (LTCC), the major transmembrane Ca2+ conductance channel, and SERCA, the sarcoplasmic reticulum (SR) Ca2+ATP-ase, which actively transports Ca2+ into the SR26.

Bottom Line: Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel.These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function.The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

View Article: PubMed Central - PubMed

Affiliation: Brigham and Women's Hospital/Harvard Medical School, Cardiovascular Division, 75 Francis Street, Thorn 11, Boston, Massachusetts 02115, USA.

ABSTRACT
Electrical gradients are critical for many biological processes, including the normal function of excitable tissues, left-right patterning, organogenesis and wound healing. The fundamental mechanisms that regulate the establishment and maintenance of such electrical polarities are poorly understood. Here we identify a gradient of electrical coupling across the developing ventricular myocardium using high-speed optical mapping of transmembrane potentials and calcium concentrations in the zebrafish heart. We excluded a role for differences in cellular excitability, connexin localization, tissue geometry and mechanical inputs, but in contrast we were able to demonstrate that non-canonical Wnt11 signals are required for the genesis of this myocardial electrical gradient. Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel. These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function. The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

Show MeSH
Related in: MedlinePlus