HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart

Fenske, Stefanie; Mader, Robert M.; Scharr, Andreas; Paparizos, Christos; Cao-Ehlker, Xiaochun; Michalakis, Stylianos; Shaltiel, Lior; Weidinger, M.; Stieber, Juliane; Feil, Susanne; Feil, Robert; Hofmann, Franz; Wahl‐Schott, Christian; Biel, Martin

doi:10.1161/circresaha.111.246173

Cited by 69 publications

(63 citation statements)

References 52 publications

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“…Possible explanations for this mismatch between the importance of the channels and their hyperpolarized voltage dependence include the production of voltage-independent leak current by hyperpolarization-activated, cyclic nucleotidesensitive (HCN) channels (45,46), hysteresis in the voltage dependence of activation (47,48), and slow activation and inactivation that could contribute to persistent opening in response to the relatively rapid voltage changes in mouse SAMs. A precedent for activity of HCN channels at positive membrane potentials is provided by the recent report of a role for HCN3 in repolarization of ventricular myocytes (49).…”

Section: Discussionmentioning

confidence: 99%

“…Candidate outward currents that could offset the reduced I Ca,L density include the rapid delayed rectifier K + current (I Kr ) and the inward rectifier Cl − current mediated by ClC-2, both of which influence MDP, APD, and repolarization in SAMs (36,54). The decrease in I f density in aged SAMs could also contribute to a reduction in repolarizing K + current, as it does in ventricular myocytes (49). We also consider it likely that aging alters Ca 2+ release from the sarcoplasmic reticulum (SR) in SAMs, a process that is known to be critical for pacemaker activity (27)(28)(29)55).…”

Section: Discussionmentioning

confidence: 99%

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Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

Larson

Clair

Sumner

et al. 2013

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

118

163

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An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in "intrinsic heart rate" (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that agedependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L-and T-type Ca 2+ currents and the "funny current" (I f ), and a hyperpolarizing shift in the voltage dependence of I f . The agedependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L-and T-type Ca 2+ currents, and I f . Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging. O ne of the most insidious aspects of growing older is an inevitable decline in maximum heart rate (mHR), which limits maximum aerobic capacity with advancing age (1-3). The decline in mHR proceeds at approximately the same rate for all individuals, without regard for lifestyle or physical fitness (4-8). For many otherwise healthy elderly people, it is the factor that ultimately restricts the ability to live independently (9, 10).The decrease in mHR with age results primarily from a parallel age-dependent decline in "intrinsic heart rate" (iHR) (11-13), which is measured during autonomic blockade, and thus reflects the spontaneous pacemaker activity of the sinoatrial node of the heart. Although it is known that the intact sinoatrial node from aged animals contracts more slowly (14, 15) and contains fewer pacemaker myocytes (16), little is known about the functional properties of individual myocytes from the sinoatrial node of the aged heart.Sinoatrial myocytes (SAMs) are highly specialized cells that serve a primarily electrical function as cardiac pacemakers via their production of spontaneous action potentials (APs). Sinoatrial APs are characterized by a spontaneous depolarization during diastole that drives the membrane potential to threshold, thereby triggering the subsequent AP. This "diastolic depolarization" (DD) phase of the sinoatrial AP results from the coordinated activit...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

Larson

Clair

Sumner

et al. 2013

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

118

163

View full text Add to dashboard Cite

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“…In addition to HCN4 and according to their transcript levels in SAN, HCN2 is expressed in mouse and HCN1 is expressed in rabbit [39] . HCN3 was recently observed in rodent ventricular myocytes [40] . As HCN3 has a lower range of activation in working cardiomyocytes, the I f current density is very small in those type of cells, which may be why it is considered as a "background current", which is in contrast to its role in SAN [41] .…”

Section: Membrane or Voltage Clock Modelmentioning

confidence: 92%

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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“…After heating at 95°C for 15 minutes followed by centrifugation at 1000g for 10 minutes to remove cell debris, the resulting supernatant was used in Western blot analysis as previously described. 28 The following antibodies were used: mouse anti-HCN1 (1:1000; Abcam, Cambridge, UK), rat anti-HCN4 (1:500; Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-HCN2 L (1:500), 11 and mouse anti-tubulin (1:2000; Dianova, Hamburg, Germany).…”

Section: Western Blotmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

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Among these channels, HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which are the molecular correlate of hyperpolarization-activated current (I f ), 14 are considered to be of particular importance. Three of the 4 members of the HCN channel family (HCN1, HCN2, and HCN4) have been identified in pacemaker cells. Quantitatively, in all vertebrates studied so far, HCN4 underlies the major fraction of SAN I f , amounting to ≈70% to 80% of the total I f . HCN4 is essential for the formation of mature pacemaker cells during embryogenesis.15 Moreover, analysis of human HCN4 channelopathies 16 and genetic mouse models 1,17,18 (see also the work by Herrmann et al 9 and Hoesl et al 10 ) suggests that this channel plays an important role in autonomic control of heart rate. Mice deficient in HCN2 display mild cardiac dysrhythmia, whereas autonomic control of heart rate is preserved in these mice. 11,19 In contrast to HCN4 and HCN2, the role of HCN1 in heart has not yet been examined. HCN1 was originally cloned from mouse brain. 20 Indeed, analysis of HCN1 knockout (KO) mice revealed that this channel is involved in the control of Background-Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND. Methods and Results-Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output. Conclusions-We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND. (Circulation. 2013;128:2585-2594.)

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HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart

Cited by 69 publications

References 52 publications

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

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

Sick Sinus Syndrome in HCN1-Deficient Mice

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