Pacemaker Current and Automatic Rhythms: Toward a Molecular Understanding

Cohen, Ira S.; Robinson, Richard B.

doi:10.1007/3-540-29715-4_2

Cited by 25 publications

(26 citation statements)

References 129 publications

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“…One of the characteristic alterations of hypertrophic hearts is the re-expression or overexpression of pacemaker channel genes thereby I f current, which may contribute significantly to the enhanced abnormality and the risk of arrhythmias under such pathological conditions [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. However, the mechanisms remained poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…This electrical remodeling process is at least partially 318 determined by a reprogramming of cardiac gene expression and the reactivation of 'fetal' cardiac genes. Among these genes are the ones encoding the ion channel proteins that generate pacemaker current I f , the hyperpolarization-activated cyclic nucleotide-gated channel (HCN) gene family [1][2][3]. The HCN family is composed of at least four members (HCN1-HCN4), of which HCN4 is believed to be the major molecular component for sinus I f and HCN2 the dominant isoform for ventricular I f .…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Control of Pacemaker Channel Genes HCN2 and HCN4 by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Lin

Xiao²,

Luo³

et al. 2009

Cell Physiol Biochem

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Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells may contribute to hypertrophic arrhythmias. The pacemaker current I_f, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in rhythmogenesis. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. However, how their expressions are controlled remained unclear. We performed a study to characterize the regulatory elements and transcriptional control of HCN2 and HCN4 genes. We identified the transcription start sites by 5’RACE and core promoter regions of these genes using luciferase reporter assay, and revealed the ubiquitous Sp1 protein as a common transactivator of HCN2 and HCN4 genes. We further unraveled robust increases in HCN2/HCN4 transcripts and protein levels, using real-time RT-PCR and Western blot analyses, in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The upregulation of HCN2 and HCN4 transcription was accompanied by pronounced elevations of Sp1 and silencing of Sp1 by siRNA prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. Our data indicate that Sp1 drives HCN2/HCN4 transcription and determines the functional level of HCN2/HCN4 mRNAs, and upregulation of Sp1 underlie the abnormal re-expression of HCN2/HCN4 genes in hypertrophied myocytes. This study also provides the first evidence for the role of Sp1 in the reactivation of ‘fetal’ cardiac genes, HCN2 and HCN4, in ventricular myocytes, and thereby in the pathological electrical remodeling in hypertrophied myocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptional Control of Pacemaker Channel Genes HCN2 and HCN4 by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Lin

Xiao²,

Luo³

et al. 2009

Cell Physiol Biochem

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“…Indeed, the pharmacological control of cardiac automaticity is now becoming an important issue in the management of ischemic heart diseases (123). Iden- tification of ion channels involved in the generation of automaticity also constitutes the basis for the development of putative genetic and cellular therapies for dysfunctions of pacemaking (94,423,424). Finally, knowledge of pacemaker mechanisms is fundamental for understanding the basis of inherited diseases of the heart rhythm.…”

Section: Introductionmentioning

confidence: 99%

Genesis and Regulation of the Heart Automaticity

Mangoni

Nargeot²

2008

Physiological Reviews

518

565

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The heart automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrical oscillations. The exact cascade of steps initiating the pacemaker cycle in automatic cells has not yet been entirely elucidated. Nevertheless, ion channels and intracellular Ca(2+) signaling are necessary for the proper setting of the pacemaker mechanism. Here, we review the current knowledge on the cellular mechanisms underlying the generation and regulation of cardiac automaticity. We discuss evidence on the functional role of different families of ion channels in cardiac pacemaking and review recent results obtained on genetically engineered mouse strains displaying dysfunction in heart automaticity. Beside ion channels, intracellular Ca(2+) release has been indicated as an important mechanism for promoting automaticity at rest as well as for acceleration of the heart rate under sympathetic nerve input. The potential links between the activity of ion channels and Ca(2+) release will be discussed with the aim to propose an integrated framework of the mechanism of automaticity.

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“…The characteristics of these channels [12,45,[78][79][80][81][82][83][84][85][86][87][88][89][90] will be briefly considered here and then the specific question as to whether they are pacemaker channels and they provide evidence supporting a pacemaker role of I f will be addressed.…”

Section: The Characteristics Of the Hcn Channelsmentioning

confidence: 99%

The vicissitudes of the pacemaker current I Kdd of cardiac purkinje fibers

Vassalle

2007

J Biomed Sci

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The mechanisms underlying the pacemaker current in cardiac tissues is not agreed upon. The pacemaker potential in Purkinje fibers has been attributed to the decay of the potassium current I (Kdd). An alternative proposal is that the hyperpolarization-activated current I (f) underlies the pacemaker potential in all cardiac pacemakers. The aim of this review is to retrace the experimental development related to the pacemaker mechanism in Purkinje fibers with reference to findings about the pacemaker mechanism in the SAN as warranted. Experimental data and their interpretation are critically reviewed. Major findings were attributed to K(+) depletion in narrow extracellular spaces which would result in a time dependent decay of the inward rectifier current I (K1). In turn, this decay would be responsible for a "fake" reversal of the pacemaker current. In order to avoid such a postulated depletion, Ba(2+) was used to block the decay of I (K1). In the presence of Ba(2+) the time-dependent current no longer reversed and instead increased with time and more so at potentials as negative as -120 mV. In this regard, the distinct possibility needs to be considered that Ba(2+) had blocked I (Kdd) (and not only I (K1)). That indeed this was the case was demonstrated by studying single Purkinje cells in the absence and in the presence of Ba(2+). In the absence of Ba(2+), I (Kdd) was present in the pacemaker potential range and reversed at E (K). In the presence of Ba(2+), I (Kdd) was blocked and I (f) appeared at potentials negative to the pacemaker range. The pacemaker potential behaves in a manner consistent with the underlying I (Kdd) but not with I (f). The fact that I (f) is activated on hyperpolarization at potential negative to the pacemaker range makes it suitable as a safety factor to prevent the inhibitory action of more negative potentials on pacemaker discharge. It is concluded that the large body of evidence reviewed proves the pacemaker role of I (Kdd) (but not of I (f)) in Purkinje fibers.

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Pacemaker Current and Automatic Rhythms: Toward a Molecular Understanding

Cited by 25 publications

References 129 publications

Transcriptional Control of Pacemaker Channel Genes <i>HCN2</i> and <i>HCN4</i> by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Transcriptional Control of Pacemaker Channel Genes <i>HCN2</i> and <i>HCN4</i> by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Genesis and Regulation of the Heart Automaticity

The vicissitudes of the pacemaker current I Kdd of cardiac purkinje fibers

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