Occurrence and Properties of the Hyperpolarization-Activated Current I
            <sub>f</sub>
            in Ventricular Myocytes From Normotensive and Hypertensive Rats During Aging

Cerbai, Elisabetta; Barbieri, Mario; Mugelli, Alessandro

doi:10.1161/01.cir.94.7.1674

Cited by 158 publications

(109 citation statements)

References 42 publications

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“…5B) are consistent with that interpretation. It is possible that a similar phenomenon occurs in the diseased ventricle, where pacemaker current magnitude also is increased (15,16). Finally, the functional effect of MiRP1 appears to be specific to that isoform, in that MinK did not affect HCN2 current in myocytes, in agreement with our previous study in oocytes (4).…”

Section: Discussionsupporting

confidence: 90%

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Qu¹,

Kryukova²,

Potapova

et al. 2004

Journal of Biological Chemistry

120

106

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MinK-related protein (MiRP1 or KCNE2) interacts with the hyperpolarization-activated, cyclic nucleotidegated (HCN) family of pacemaker channels to alter channel gating in heterologous expression systems. Given the high expression levels of MiRP1 and HCN subunits in the cardiac sinoatrial node and the contribution of pacemaker channel function to impulse initiation in that tissue, such an interaction could be of considerable physiological significance. However, the functional evidence for MiRP1/HCN interactions in heterologous expression studies has been accompanied by inconsistencies between studies in terms of the specific effects on channel function. To evaluate the effect of MiRP1 on HCN expression and function in a physiological context, we used an adenovirus approach to overexpress a hemagglutinin (HA)-tagged MiRP1 (HAMiRP1) and HCN2 in neonatal rat ventricular myocytes, a cell type that expresses both MiRP1 and HCN2 message at low levels. HA-MiRP1 co-expression with HCN2 resulted in a 4-fold increase in maximal conductance of pacemaker currents compared with HCN2 expression alone. HCN2 activation and deactivation kinetics also changed, being significantly more rapid for voltages between ؊60 and ؊95 mV when HA-MiRP1 was co-expressed with HCN2. However, the voltage dependence of activation was not affected. Co-immunoprecipitation experiments demonstrated that expressed HA-MiRP1 and HCN2, as well as endogenous MiRP1 and HCN2, co-assemble in ventricular myocytes. The results indicate that MiRP1 acts as a ␤ subunit for HCN2 pacemaker channel subunits and alters channel gating at physiologically relevant voltages in cardiac cells.MinK-related protein (MiRP1 or KCNE2) is purported to be a ␤ subunit for several voltage-gated potassium channels, including the rapid delayed rectifier (1), slow delayed rectifier (2), and transient outward current (3). In addition, we have reported that it can act as a ␤ subunit for the hyperpolarizationactivated, cyclic nucleotide-gated (HCN) 1 family of pacemaker channels (4). We found that co-expression of MiRP1 with HCN1 or HCN2 in Xenopus oocytes resulted in larger and more rapidly activating currents than when either HCN isoform was expressed alone but that MiRP1 did not shift the midpoint of activation of either isoform. Further, co-immunoprecipitation experiments involving HA-tagged MiRP1 and HCN1 demonstrated that the two proteins interact when co-expressed in oocytes.A more recent study demonstrated MiRP1 interaction with the HCN4 isoform. Here, co-expression with MiRP1, either in oocytes or Chinese hamster ovary cells, also resulted in increased current amplitude, but this was associated with slowing of kinetics and a negative shift of the midpoint of activation (5). However, another laboratory did not detect any effect of MiRP1 when co-expressed in HEK293 cells with either HCN4 or an HCN1-HCN4 tandem construct (6). Finally, a study of MiRP1 and HCN2 co-expression in Chinese hamster ovary cells reported a reduced time-dependent current component and increased instantaneous ...

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Section: Discussionsupporting

confidence: 90%

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Qu¹,

Kryukova²,

Potapova

et al. 2004

Journal of Biological Chemistry

120

106

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“…5A. In this cell, I f began to activate around Ϫ80 mV, close to the previously reported values (5,21).…”

Section: Hyperpolarization-induced Casupporting

confidence: 89%

Calcium influx through I_f channels in rat ventricular myocytes

Yu¹,

Chen²,

Zhou³

et al. 2007

American Journal of Physiology-Cell Physiology

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The hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, or cardiac ( If)/neuronal ( Ih) time- and voltage-dependent inward cation current channels, are conventionally considered as monovalent-selective channels. Recently we discovered that calcium ions can permeate through HCN4 and Ih channels in neurons. This raises the possibility of Ca2+ permeation in If, the Ih counterpart in cardiac myocytes, because of their structural homology. We performed simultaneous measurement of fura-2 Ca2+ signals and whole cell currents produced by HCN2 and HCN4 channels (the 2 cardiac isoforms present in ventricles) expressed in HEK293 cells and by If in rat ventricular myocytes. We observed Ca2+ influx when HCN/ If channels were activated. Ca2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium, an If channel blocker, inhibited If and Ca2+ influx at the same time. Quantitative analysis revealed that Ca2+ flux contributed to ∼0.5% of current produced by the HCN2 channel or If. The associated increase in Ca2+ influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which If current density is higher than that of normotensive rat ventricle. In the absence of EGTA (a Ca2+ chelator), preactivation of If channels significantly reduced the action potential duration, and the effect was blocked by another selective If channel blocker, ZD-7288. In the presence of EGTA, however, preactivation of If channels had no effects on action potential duration. Our data extend our previous discovery of Ca2+ influx in Ih channels in neurons to If channels in cardiac myocytes.

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“…Notably, an association between hypertrophy and arrhythmia was identified despite only mild to moderate increases in LVWT in MHC 403/ϩ mice. The mechanism by which myocyte enlargement increases arrhythmic risk may relate to changes in intrinsic automaticity, in that other experimental models of hypertrophied myocytes exhibit reexpression of pacemaker currents (36) and enhanced prolongation of the action potential by a down-regulation of the main outward current I to (37,38). Calcium signaling may also play a role in arrhythmia vulnerability, both because calcium handling is directly perturbed by sarcomere mutations (26) and because calcium cycling increases with enhanced contractility (39,40).…”

Section: Resultsmentioning

confidence: 99%

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

Wolf

Moskowitz

Arno

et al. 2005

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

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Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.fibrosis ͉ somatic modifiers ͉ disarray ͉ electrophysiology ͉ left ventrical wall thickness

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Occurrence and Properties of the Hyperpolarization-Activated Current I _f in Ventricular Myocytes From Normotensive and Hypertensive Rats During Aging

Cited by 158 publications

References 42 publications

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Calcium influx through I_f channels in rat ventricular myocytes

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

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Occurrence and Properties of the Hyperpolarization-Activated Current I f in Ventricular Myocytes From Normotensive and Hypertensive Rats During Aging

Cited by 158 publications

References 42 publications

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Calcium influx through If channels in rat ventricular myocytes

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

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Product

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Occurrence and Properties of the Hyperpolarization-Activated Current I _f in Ventricular Myocytes From Normotensive and Hypertensive Rats During Aging

Calcium influx through I_f channels in rat ventricular myocytes