title: Kv4.3-Encoded Fast Transient Outward Current Is Presented in Kv4.2 Knockout Mouse Cardiomyocytes.
abstract: Gradients of the fast transient outward K+ current (Ito,f) contribute to heterogeneity of ventricular repolarization in a number of species. Cardiac Ito,f levels and gradients change notably with heart disease. Human cardiac Ito,f appears to be encoded by the Kv4.3 pore-forming α-subunit plus the auxiliary KChIP2 β-subunit while mouse cardiac Ito,f requires Kv4.2 and Kv4.3 α-subunits plus KChIP2. Regional differences in cardiac Ito,f are associated with expression differences in Kv4.2 and KChIP2. Although Ito,f was reported to be absent in mouse ventricular cardiomyocytes lacking the Kv4.2 gene (Kv4.2-/-) when short depolarizing voltage pulses were used to activate voltage-gated K+ currents, in the present study, we showed that the use of long depolarization steps revealed a heteropodatoxin-sensitive Ito,f (at ~40% of the wild-type levels). Immunohistological studies further demonstrated membrane expression of Kv4.3 in Kv4.2-/- cardiomyocytes. Transmural Ito,f gradients across the left ventricular wall were reduced by ~3.5-fold in Kv4.2-/- heart, compared to wild-type. The Ito,f gradient in Kv4.2-/- hearts was associated with gradients in KChIP2 mRNA expression while in wild-type there was also a gradient in Kv4.2 expression. In conclusion, we found that Kv4.3-based Ito,f exists in the absence of Kv4.2, although with a reduced transmural gradient. Kv4.2-/- mice may be a useful animal model for studying Kv4.3-based Ito,f as observed in humans.
authors.affiliation: The Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, University Health Network, Toronto, Ontario, Canada; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Kyoung-Han
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Physiology & Biophysics, University at Buffalo, the State University of New York, Buffalo, New York, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morales
authors.affiliation: The Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; The Departments of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.affiliation: The Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013111:Spider Venoms / Q000494:pharmacology
chemical_list: C524386:HpTx-2 protein, Heteropoda venatoria; D051605:Kv Channel-Interacting Proteins; D026902:Potassium Channel Blockers; D021122:Protein Subunits; D051672:Shal Potassium Channels; D013111:Spider Venoms