The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium

Remme, CA; Verkerk, Arie O.; Hoogaars, Willem M.H.; Aanhaanen, Wim T.J.; Scicluna, Brendon P.; Annink, C.; Hoff, Maurice J.B. van den; Wilde, Arthur A.M.; Veen, Toon A.B. van; Veldkamp, Marieke W.; Bakker, Jacques M.T. de; Christoffels, Vincent M.; Bezzina, Connie R.

doi:10.1007/s00395-009-0012-8

Cited by 113 publications

(101 citation statements)

References 49 publications

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“…The absence of sustained idioventricular rhythm after AV block agrees well with the notions that in mice HCN4 channels are highly expressed also in physiological conditions in the HisPurkinje system (22) and that the MHC promoter is active in the cardiac conduction tissue (23).…”

Section: Discussionsupporting

confidence: 87%

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

Baruscotti

Bucchi

Viscomi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

247

232

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Cardiac pacemaking generation and modulation rely on the coordinated activity of several processes. Although a wealth of evidence indicates a relevant role of the I f ("funny," or pacemaker) current, whose molecular constituents are the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and particularly HCN4, work with mice where Hcn genes were knocked out, or functionally modified, has challenged this view. However, no previous studies used a cardiac-specific promoter to induce HCN4 ablation in adult mice. We report here that, in an inducible and cardiac-specific HCN4 knockout (ciHCN4-KO) mouse model, ablation of HCN4 consistently leads to progressive development of severe bradycardia (∼50% reduction of original rate) and AV block, eventually leading to heart arrest and death in about 5 d. In vitro analysis of sinoatrial node (SAN) myocytes isolated from ciHCN4-KO mice at the mean time of death revealed a strong reduction of both the I f current (by ∼70%) and of the spontaneous rate (by ∼60%). In agreement with functional results, immunofluorescence and Western blot analysis showed reduced expression of HCN4 protein in SAN tissue and cells. In ciHCN4-KO animals, the residual I f was normally sensitive to β-adrenergic receptor (β-AR) modulation, and the permanence of rate response to β-AR stimulation was observed both in vivo and in vitro. Our data show that cardiac HCN4 channels are essential for normal heart impulse generation and conduction in adult mice and support the notion that dysfunctional HCN4 channels can be a direct cause of rhythm disorders. This work contributes to identifying the molecular mechanism responsible for cardiac pacemaking.funny current | heart rate | sinoatrial node | atrioventricular node | chronotropism T he degree of complexity of the processes involved in pacemaking and their individual contributions is still a hotly debated issue (1, 2). Despite this complexity, and granting the fact that perturbation of any participating mechanism can affect rate, there is evidence for a functional specificity of "funny" (f)-channels in mediating generation and physiological control of pacemaker activity.Native f-channels are encoded by four hyperpolarizationactivated, cyclic nucleotide-gated channel genes (Hcn1-4), of which Hcn4 is by far the most highly expressed in the cardiac pacemaker regions of different species (3-6). HCN4 contributes 80% of total HCN mRNA in rabbit and mouse sinoatrial node (SAN), the remaining 20% being a combination of HCN2 and HCN1, with species-dependent relative abundance (4,5,(7)(8)(9). Evidence for the role of f/HCN4 channels in pacemaking relies on several experimental data (10):i) The "funny" (I f ) current and pacemaker activity are correlated; i.e., functional expression of f-channels is restricted to pacemaking regions [SAN, atrioventricular node (AVN), and the ventricular conduction system], demonstrating a commitment to regulation of pacemaker activity. This correlation exists not only in the adult but also throughout development, such that ...

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Section: Discussionsupporting

confidence: 87%

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

Baruscotti

Bucchi

Viscomi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

247

232

View full text Add to dashboard Cite

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“…Here, it successfully competes with Tbx3 for occupation of binding sites of 'conduction genes' such as Cx40 and Scn5a. This leads to strong Scn5a expression in the AVB and BB from the outset (Remme et al, 2009), and to induction of Cx40 expression in the AVB during the foetal period, which seems to correlate with the AVB acquiring its function to primarily conduct the impulse. In embryos deficient for the bHLH transcription factor Hey2, the transmural expression of Tbx5, Cx40 and Scn5a, which are enriched in the trabecular component of the developing ventricle, is expanded into the compact myocardium (Xin et al, 2007;Koibuchi and Chin, 2007;Fischer et al, 2005;Bezzina et al, 2013).…”

Section: Molecular Programming Of the Vcsmentioning

confidence: 98%

The formation and function of the cardiac conduction system

2016

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The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. CCS development involves complex regulatory networks that act in stage-, tissue-and dose-dependent manners, and recent findings indicate that the activity of these networks is sensitive to common genetic variants associated with cardiac arrhythmias. Here, we review how these findings have provided novel insights into the regulatory mechanisms and transcriptional networks underlying CCS formation and function.

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“…Histologically, this proliferative "pre-chamber myocardium" contains well-organized sarcomeres and developed endoplasmic reticulum. Molecularly, the extinction of Tbx3 leads to the appearance of "high conductance" proteins [11][12][13] , such as the connexins Cx40 and Cx43 [14] , and the replacement of the Land T-type Ca 2+ channels by the fast voltage-activated sodium channel Scn5a (Nav1.5) [15] . HCN4 expression is also strongly decreased in the working myocardium, as this tissue loses its intrinsic pacemaker activity [16][17][18] .…”

Section: Development Of the Human Cardiac Conduction Systemmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium

Cited by 113 publications

References 49 publications

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

The formation and function of the cardiac conduction system

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

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