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PLoS One
2010 Feb 02;52:e9021. doi: 10.1371/journal.pone.0009021.
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Differential expression of hERG1 channel isoforms reproduces properties of native I(Kr) and modulates cardiac action potential characteristics.
Larsen AP
,
Olesen SP
.
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The repolarizing cardiac rapid delayed rectifier current, I(Kr), is composed of ERG1 channels. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to I(Kr). Marked heterogeneity in the kinetic properties of native I(Kr) has been described. We hypothesized that the heterogeneity of native I(Kr) can be reproduced by differential expression of ERG1a and ERG1b isoforms. Furthermore, the functional consequences of differential expression of ERG1 isoforms were explored as a potential mechanism underlying native heterogeneity of action potential duration (APD) and restitution. The results show that the heterogeneity of native I(Kr) can be reproduced in heterologous expression systems by differential expression of ERG1a and ERG1b isoforms. Characterization of the macroscopic kinetics of ERG1 currents demonstrated that these were dependent on the relative abundance of ERG1a and ERG1b. Furthermore, we used a computational model of the ventricular cardiomyocyte to show that both APD and the slope of the restitution curve may be modulated by varying the relative abundance of ERG1a and ERG1b. As the relative abundance of ERG1b was increased, APD was gradually shortened and the slope of the restitution curve was decreased. Our results show that differential expression of ERG1 isoforms may explain regional heterogeneity of I(Kr) kinetics. The data demonstrate that subunit dependent changes in channel kinetics are important for the functional properties of ERG1 currents and hence I(Kr). Importantly, our results suggest that regional differences in the relative abundance of ERG1 isoforms may represent a potential mechanism underlying the heterogeneity of both APD and APD restitution observed in mammalian hearts.
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20126398
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Figure 1. Topology of the hERG1 Markov model.The hERG1 Markov model developed by Fink et al. [15], consists of three closed states (C1-C3), an open state (O) and an inactivated state (I). Allowed transitions between states are indicated with arrows. The transition rates are indicated above or below the corresponding transitions.
Figure 2. The relative abundance of hERG1a and hERG1b determines the âpeak potentialâ in mammalian cells.A, Representative recordings of hERG1a, hERG1b and hERG1a/b channels expressed in HEK293 cells are shown. Currents were recorded using the protocol depicted in the inset. Only currents recorded during the ramp are shown. For comparison, currents were normalized to the maximum peak current during the ramp and plotted against the command voltage. The dotted lines indicate the potential where the currents peaked (âpeak potentialâ) and are also used to indicate the expressed channels. B, Summary data of the variation in âpeak potentialâ. For comparison, the peak amplitude was normalized to an estimate of the number of channels (N) and plotted as a function of the âpeak potentialâ.
Figure 3. The âpeak potentialâ is directly dependent on the relative abundance of hERG1 isoforms.A, Representative recordings from X. laevis oocytes injected with different ratios of hERG1 isoforms. The same protocol as shown in figure 2A was used. Only currents recorded during the ramp are shown. For comparison, currents were normalized to the maximum peak current during the ramp and plotted against the command voltage. The dotted lines indicate the potential where the currents peaked (âpeak potentialâ) and are also used to indicate the isoform ratio (in % of hERG1b abundance). B, Summary data of the variation in âpeak potentialâ. For comparison, the peak amplitude was normalized to N and plotted as a function of the âpeak potentialâ.
Figure 4. The experimental data is reproduced by a hERG1 Markov model.A, The effect of changes in transition rates, representing a gradual increase in the relative abundance of hERG1b, on simulated hERG1 currents. The transition rates of hERG1 channel activation (α3), deactivation (β3) and recovery from inactivation (β4) were modified to represent a gradual increase in the relative abundance of hERG1b (see table S2 for details). The model was subjected to the same voltage protocol as in figure 2A. Only currents recorded during the ramp are shown. For comparison, currents were normalized to the maximum peak current during the ramp and plotted against the command voltage. The dotted lines indicate the potential where the currents peaked (âpeak potentialâ) and are also used to indicate the isoform ratio (in % of hERG1b abundance). B, The variation in âpeak potentialâ amplitude is shown as a function of âpeak potentialâ. The data were not normalized as the number of channels in the model remained constant.
Figure 5. Action potential duration is modulated by the relative abundance of hERG1a and hERG1b.A, Steady-state action potentials simulated by the modified ten Tusscher (TTF) model paced at a basic cycle length (BCL) of 1000 ms. The transition rates of hERG1 channel activation (α3), deactivation (β3) and recovery from inactivation (β4) were modified to represent a gradual increase in the relative abundance of hERG1b (see table S2 for details). B, Simulated IKr corresponding to the action potentials shown in A. Legend is the same as in A. C and D, Channel state occupancy during the action potential is shown for the open and inactivated states respectively. Legend is the same as in A.
Figure 6. Restitution slope is modulated by the relative abundance of hERG1a and hERG1b.A, Single-cell action potential restitution. The restitution curves were obtained using an S1-S2 restitution protocol measured at a BCL of 1000 ms. The action potential duration (APD90) is plotted as a function of the diastolic interval (DI). The transition rates of hERG1 channel activation (α3), deactivation (β3) and recovery from inactivation (β4) were modified to represent a gradual increase in the relative abundance of hERG1b (see table S2 for details). B, The slopes of the restitution curves were calculated by differentiation of single-exponential functions fitted to the curves in A and plotted as a function of DI.
Baláti,
Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres.
1998, Pubmed
Baláti,
Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres.
1998,
Pubmed
Brugada,
Sudden death associated with short-QT syndrome linked to mutations in HERG.
2004,
Pubmed
Bryant,
Regional differences in the delayed rectifier current (IKr and IKs) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig.
1998,
Pubmed
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
Fink,
Contributions of HERG K+ current to repolarization of the human ventricular action potential.
2008,
Pubmed
Garny,
CELLULAR OPEN RESOURCE (COR): current status and future directions.
2009,
Pubmed
Gintant,
Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization.
2000,
Pubmed
Hua,
Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes.
2004,
Pubmed
Jespersen,
Dual-function vector for protein expression in both mammalian cells and Xenopus laevis oocytes.
2002,
Pubmed
,
Xenbase
Jones,
Cardiac IKr channels minimally comprise hERG 1a and 1b subunits.
2004,
Pubmed
Karma,
Electrical alternans and spiral wave breakup in cardiac tissue.
1994,
Pubmed
Kirchberger,
Effects of TRH on heteromeric rat erg1a/1b K+ channels are dominated by the rerg1b subunit.
2006,
Pubmed
Larsen,
Characterization of hERG1a and hERG1b potassium channels-a possible role for hERG1b in the I (Kr) current.
2008,
Pubmed
,
Xenbase
Laurita,
Modulation of ventricular repolarization by a premature stimulus. Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart.
1996,
Pubmed
Lees-Miller,
Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts.
1997,
Pubmed
,
Xenbase
Liu,
Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell.
1995,
Pubmed
London,
Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current.
1997,
Pubmed
,
Xenbase
Luo,
Genomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes.
2008,
Pubmed
Nash,
Whole heart action potential duration restitution properties in cardiac patients: a combined clinical and modelling study.
2006,
Pubmed
Riccio,
Electrical restitution and spatiotemporal organization during ventricular fibrillation.
1999,
Pubmed
Sale,
Physiological properties of hERG 1a/1b heteromeric currents and a hERG 1b-specific mutation associated with Long-QT syndrome.
2008,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Szabó,
Asymmetrical distribution of ion channels in canine and human left-ventricular wall: epicardium versus midmyocardium.
2005,
Pubmed
ten Tusscher,
Alternans and spiral breakup in a human ventricular tissue model.
2006,
Pubmed
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Tseng,
I(Kr): the hERG channel.
2001,
Pubmed
Viswanathan,
Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study.
1999,
Pubmed
Wang,
Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels.
2000,
Pubmed
,
Xenbase
Weiss,
Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation.
1999,
Pubmed
Yan,
Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations.
1998,
Pubmed
Yue,
Global endocardial electrical restitution in human right and left ventricles determined by noncontact mapping.
2005,
Pubmed
Zeng,
Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization.
1995,
Pubmed
