title: Wnt signalling suppresses voltage-dependent Na⁺ channel expression in postnatal rat cardiomyocytes.
abstract: Wnt signalling plays crucial roles in heart development, but is normally suppressed postnatally. In arrhythmogenic conditions, such as cardiac hypertrophy and heart failure, Wnt signalling is reactivated. To explore the potential role of Wnt signalling in arrhythmogenic electrical remodelling, we examined voltage-dependent ion channels in cardiomyocytes. Treatment of neonatal rat ventricular myocytes with either recombinant Wnt3a protein or CHIR-99021 (CHIR, a glycogen synthase kinase-3β inhibitor) caused a dose-dependent increase in Wnt target gene expression (Axin2 and Lef1), indicating activation of the Wnt/β-catenin pathway. Cardiac Na(+) current (INa) density was reduced by Wnt3a (-20 ± 4 vs. control -59 ± 7 pA pF(-1) , at -30 mV) or CHIR (-22 ± 5 pA pF(-1) ), without changes in steady-state activation, inactivation or repriming kinetics. Wnt3a and CHIR also produced dose-dependent reductions in the mRNA level of Scn5a (the cardiac Na(+) channel α subunit gene), as well as a 56% reduction (by Wnt3a) in the Nav 1.5 protein level. Consistent with INa reduction, action potentials in Wnt3a-treated neonatal rat ventricular myocytes had a lower upstroke amplitude (91 ± 3 vs. control 137 ± 2 mV) and decreased maximum upstroke velocity (70 ± 10 vs. control 163 ± 15 V s(-1)). In contrast, inward rectifier K(+) current and L-type Ca(2+) channels were not affected by Wnt3a treatment. Taken together, our data indicate that the Wnt/β-catenin pathway suppresses INa in postnatal cardiomyocytes and may contribute to ion channel remodelling in heart disease.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liang
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Cho
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C572053:Axin2 protein, rat; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; C497575:Lef1 protein, rat; D051821:Lymphoid Enhancer-Binding Factor 1; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024661:Potassium Channels, Inwardly Rectifying; C568322:Scn5a protein, rat; D060509:Wnt3A Protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3