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β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants
The human ventricular cardiomyocyte transient outward K(+) current (I(to)) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac I(to) is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, div...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296356/ https://www.ncbi.nlm.nih.gov/pubmed/28228734 http://dx.doi.org/10.3389/fphys.2017.00066 |
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author | Abbott, Geoffrey W. |
author_facet | Abbott, Geoffrey W. |
author_sort | Abbott, Geoffrey W. |
collection | PubMed |
description | The human ventricular cardiomyocyte transient outward K(+) current (I(to)) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac I(to) is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology. |
format | Online Article Text |
id | pubmed-5296356 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-52963562017-02-22 β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants Abbott, Geoffrey W. Front Physiol Physiology The human ventricular cardiomyocyte transient outward K(+) current (I(to)) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac I(to) is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology. Frontiers Media S.A. 2017-02-08 /pmc/articles/PMC5296356/ /pubmed/28228734 http://dx.doi.org/10.3389/fphys.2017.00066 Text en Copyright © 2017 Abbott. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Abbott, Geoffrey W. β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title | β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title_full | β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title_fullStr | β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title_full_unstemmed | β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title_short | β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants |
title_sort | β subunits functionally differentiate human kv4.3 potassium channel splice variants |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296356/ https://www.ncbi.nlm.nih.gov/pubmed/28228734 http://dx.doi.org/10.3389/fphys.2017.00066 |
work_keys_str_mv | AT abbottgeoffreyw bsubunitsfunctionallydifferentiatehumankv43potassiumchannelsplicevariants |