Hyperpolarization-activated Cyclic Nucleotide-gated Channel 1 Is a Molecular Determinant of the Cardiac Pacemaker Current I f

Moroni, Anna; Gorza, Luisa; Beltrame, Mônica; Gravante, Biagio; Vaccari, Thomas; Bianchi, Marco E.; Altomare, Claudia; Longhi, Renato; Heurteaux, Catherine; Vitadello, Maurizio; Malgaroli, Antonio; DiFrancesco, Dario

doi:10.1074/jbc.m100830200

Cited by 95 publications

(68 citation statements)

References 45 publications

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“…180 HCN1 and HCN3 were not detected in the ventricle. 19,21 Low-level HCN expression in the ventricle is consistent with its lack of automaticity.…”

Section: Molecular Basismentioning

confidence: 83%

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

Schram

Pourrier

Melnyk

et al. 2002

Circulation Research

367

283

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Abstract-The cardiac electrical system is designed to ensure the appropriate rate and timing of contraction in all regions of the heart, which are essential for effective cardiac function. Well-controlled cardiac electrical activity depends on specialized properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Cardiac electrical specialization was first recognized in the mid 1800s, but over the past 15 years, an enormous amount has been learned about how specialization is achieved by differential expression of cardiac ion channels. More recently, many aspects of the molecular basis have been revealed. Although the field is potentially vast, an appreciation of key elements is essential for any clinician or researcher wishing to understand modern cardiac electrophysiology. This article reviews the major regionally determined features of cardiac electrical function, discusses underlying ionic bases, and summarizes present knowledge of ion channel subunit distribution in relation to functional specialization. Key Words: ion channels Ⅲ molecular biology Ⅲ conduction Ⅲ cardiac arrhythmias Ⅲ antiarrhythmic drugs C ardiac function depends on the appropriate timing of contraction in various regions, as well as on appropriate heart rate. To subserve these functions, electrical activity in each region is adapted to its specialized function. Regionally specialized cardiac electrical function was recognized in the mid 1800s, when Stannius 1 demonstrated that ligatures in the superior vena caval sinus region of the frog caused cardiac asystole, with the sinus continuing to beat. With the widespread application to cardiac ion channel study of patchclamp methodologies in the 1980s and molecular biology in the 1990s, many underlying mechanisms have been unraveled. The present article reviews the major regionally determined features of cardiac electrical function and the present knowledge regarding ionic and molecular bases. Overview of Regional Functional SpecificityFigure 1 illustrates typical regional action potential (AP) properties in the heart. The normal cardiac impulse originates in the sinoatrial node (SAN) and propagates through the atria to reach the atrioventricular node (AVN). From the AVN, electrical activity passes rapidly through the cable-like HisPurkinje system to reach the ventricles, triggering cardiac pumping action. Figure 2 shows the ionic currents involved in a schematic cardiac AP, provides standard abbreviations for currents and their corresponding subunits, and summarizes principal localization data discussed elsewhere in the present review. Ionic and Molecular Basis of Functional Specificity Sinoatrial Node Cellular Electrophysiology and FunctionThe SAN, located in the right atrial (RA) roof between the venae cavae, 2 is specialized for physiological pacemaker function. Heart rate control is achieved through autonomic regulation of SAN pacemaking. SAN APs have a relatively positive maximum diastolic potential (MDP...

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“…180 HCN1 and HCN3 were not detected in the ventricle. 19,21 Low-level HCN expression in the ventricle is consistent with its lack of automaticity.…”

Section: Molecular Basismentioning

confidence: 83%

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

Schram

Pourrier

Melnyk

et al. 2002

Circulation Research

367

283

View full text Add to dashboard Cite

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“…hHCN1 mRNA was not detected in human fetal brain. Because HCN1 and HCN3 are potential pacemaker channels, expression in cardiac tissues was also expected, as has been described at least for HCN1 in other species (19,20) and recently for HCN3 in mouse heart (16). However, neither HCN1 nor HCN3 mRNAs could be detected in human heart.…”

Section: Low Overall Expression Of Hcn3 In Humanmentioning

confidence: 87%

Functional Expression of the Human HCN3 Channel

Stieber¹,

Stöckl²,

Herrmann³

et al. 2005

Journal of Biological Chemistry

128

116

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Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels underlie the inward pacemaker current, termed I f /I h , in a variety of tissues. Many details are known for the HCN subtypes 1, 2, and 4. We now successfully cloned the cDNA for HCN3 from human brain and compared the electrophysiological properties of hHCN3 to the other three HCN subtypes. Overexpression of human HCN3 channels in HEK293 cells resulted in a functional channel protein. Similar to hHCN2 channels, hHCN3 channels are activated with a rather slow time constant of 1244 ؎ 526 ms at ؊100 mV, which is a greater time constant than that of HCN1 but a smaller one than that of HCN4 channels. The membrane potential for half-maximal activation V1 ⁄ 2 was ؊77 ؎ 5.4 mV, and the reversal potential E rev was ؊20.5 ؎ 4 mV, resulting in a permeability ratio P Na /P K of 0.3. Like all other HCNs, hHCN3 was inhibited rapidly and reversibly by extracellular cesium and slowly and irreversibly by extracellular applied ZD7288. Surprisingly, the human HCN3 channel was not modulated by intracellular cAMP, a hallmark of the other known HCN channels. Sequence comparison revealed >80% homology of the transmembrane segments, the pore region, and the cyclic nucleotide binding domain of hHCN3 with the other HCN channels. The missing response to cAMP distinguishes human HCN3 from both the well cAMP responding HCN subtypes 2 and 4 and the weak responding subtype 1.Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) 2 channels are thought to underlie the native pacemaker current, termed I f or I h , in the heart and brain where these channels contribute to the control of the resting membrane potential and to the rhythmic activity of excitable cells (1-4). Four mammalian genes encoding HCN channels have been identified to date (5-7). Electrophysiological studies of the three expressed HCN (HCN1, -2, and -4) channels showed (8) that each channel is activated voltage-dependent upon membrane hyperpolarization with distinct activation kinetics (5, 9, 10). Activation of the HCN channels is directly modulated by cyclic nucleotides (11). However, the modulatory effect depends on the subtype (12, 13); activation of HCN2 and HCN4 is accelerated much more by cAMP than that of HCN1 channels. Similarly, cAMP shifts the membrane potential for activation to a largerextentforHCN2andHCN4thanforHCN1.cAMPmodulationismediated by direct binding of cAMP to a cyclic nucleotide binding domain (CNBD) located in the intracellular C terminus, thereby releasing the inhibitory effect of this C terminus on channel activation (13-15).The functional expression of HCN3 channels proved to be difficult. Expression of the murine HCN3 in HEK293 cells or similar systems resulted in very small and unstable currents. Only recently, expression of the murine HCN3 channel was improved by using a lentiviral-based approach (16). Thus, information about the basic biophysical and pharmacological properties of HCN3 channels, in comparison to the other HCN channels, is limited (5,8,16,17). Esp...

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“…21,22 However, there is also increasing evidence that HCN1 is expressed in heart. In the rabbit SAN, for example, RNase-protection assay and immunolabeling data 23,24 indicate significant expression of HCN1. On the basis of heterologous expression data and electrophysiological studies, it was speculated that HCN1, together with HCN4, contributes to native I f in rabbit SAN.…”

mentioning

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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Hyperpolarization-activated Cyclic Nucleotide-gated Channel 1 Is a Molecular Determinant of the Cardiac Pacemaker Current I f

Cited by 95 publications

References 45 publications

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

Functional Expression of the Human HCN3 Channel

Sick Sinus Syndrome in HCN1-Deficient Mice

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