Differential Expression of hERG1 Channel Isoforms Reproduces Properties of Native IKr and Modulates Cardiac Action Potential Characteristics 英文参考文献.docVIP

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Differential Expression of hERG1 Channel Isoforms Reproduces Properties of Native IKr and Modulates Cardiac Action Potential Characteristics 英文参考文献.doc

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Differential Expression of hERG1 Channel Isoforms Reproduces Properties of Native IKr and Modulates Cardiac Action Potential Characteristics 英文参考文献

DifferentialExpressionofhERG1ChannelIsoforms ReproducesPropertiesofNativeIKr andModulates CardiacActionPotentialCharacteristics AndersPeterLarsen*,S?ren-PeterOlesen TheDanishNationalResearchFoundationCentreforCardiacArrhythmia,DepartmentofBiomedicalSciences,UniversityofCopenhagen,Copenhagen,Denmark Abstract Background: The repolarizing cardiac rapid delayed rectifier current, IKr, is composed of ERG1 channels. It has been suggestedthattwoisoformsoftheERG1protein,ERG1aandERG1b,bothcontributetoIKr.Markedheterogeneityinthe kineticpropertiesofnativeIKrhasbeendescribed.WehypothesizedthattheheterogeneityofnativeIKrcanbereproduced by differential expression of ERG1a and ERG1b isoforms. Furthermore, the functional consequences of differential expressionofERG1isoformswereexploredasapotentialmechanismunderlyingnativeheterogeneityofactionpotential duration(APD)andrestitution. Methodology/PrincipalFindings:TheresultsshowthattheheterogeneityofnativeIKrcanbereproducedinheterologous expressionsystemsbydifferentialexpressionofERG1aandERG1bisoforms.Characterizationofthemacroscopickineticsof ERG1currentsdemonstratedthattheseweredependentontherelativeabundanceofERG1aandERG1b.Furthermore,we usedacomputationalmodeloftheventricularcardiomyocytetoshowthatbothAPDandtheslopeoftherestitutioncurve may be modulated by varying the relative abundance of ERG1a and ERG1b. As the relative abundance of ERG1b was increased,APDwasgraduallyshortenedandtheslopeoftherestitutioncurvewasdecreased. Conclusions/Significance: Our results show that differential expression of ERG1 isoforms may explain regional heterogeneity of IKr kinetics. The data demonstrate that subunit dependent changes in channel kinetics are important forthefunctionalpropertiesofERG1currentsandhenceIKr.Importantly,ourresultssuggestthatregionaldifferencesinthe relativeabundanceofERG1isoformsmayrepresentapotentialmechanismunderlyingtheheterogeneityofbothAPDand APDrestitutionobservedinmammalianhearts. Citation: Larsen AP, Olesen S-P (