Cargando…

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss‐ and gain‐of‐function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (I (h)...

Descripción completa

Detalles Bibliográficos
Autores principales: Butler, Andrew, Zhang, Yihong, Stuart, Alan G., Dempsey, Christopher E., Hancox, Jules C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119704/
https://www.ncbi.nlm.nih.gov/pubmed/30175559
http://dx.doi.org/10.14814/phy2.13845
_version_ 1783352115524009984
author Butler, Andrew
Zhang, Yihong
Stuart, Alan G.
Dempsey, Christopher E.
Hancox, Jules C.
author_facet Butler, Andrew
Zhang, Yihong
Stuart, Alan G.
Dempsey, Christopher E.
Hancox, Jules C.
author_sort Butler, Andrew
collection PubMed
description The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss‐ and gain‐of‐function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (I (h) (ERG)) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on I (h) (ERG) profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current–voltage (I–V) relation for I (h) (ERG) exhibited a marked right‐ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented I (h) (ERG), which also peaked much earlier during the AP plateau than did wild‐type (WT) I (h) (ERG). Instantaneous I–V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance‐voltage relation showed an earlier and more sustained rise in S631A compared to WT I (h) (ERG) conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted I (h) (ERG) in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 μmol/L) against S631A I (h) (ERG). Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.
format Online
Article
Text
id pubmed-6119704
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-61197042018-09-05 Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome Butler, Andrew Zhang, Yihong Stuart, Alan G. Dempsey, Christopher E. Hancox, Jules C. Physiol Rep Original Research The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss‐ and gain‐of‐function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (I (h) (ERG)) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on I (h) (ERG) profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current–voltage (I–V) relation for I (h) (ERG) exhibited a marked right‐ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented I (h) (ERG), which also peaked much earlier during the AP plateau than did wild‐type (WT) I (h) (ERG). Instantaneous I–V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance‐voltage relation showed an earlier and more sustained rise in S631A compared to WT I (h) (ERG) conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted I (h) (ERG) in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 μmol/L) against S631A I (h) (ERG). Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation. John Wiley and Sons Inc. 2018-09-02 /pmc/articles/PMC6119704/ /pubmed/30175559 http://dx.doi.org/10.14814/phy2.13845 Text en © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Butler, Andrew
Zhang, Yihong
Stuart, Alan G.
Dempsey, Christopher E.
Hancox, Jules C.
Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title_full Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title_fullStr Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title_full_unstemmed Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title_short Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
title_sort action potential clamp characterization of the s631a herg mutation associated with short qt syndrome
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119704/
https://www.ncbi.nlm.nih.gov/pubmed/30175559
http://dx.doi.org/10.14814/phy2.13845
work_keys_str_mv AT butlerandrew actionpotentialclampcharacterizationofthes631ahergmutationassociatedwithshortqtsyndrome
AT zhangyihong actionpotentialclampcharacterizationofthes631ahergmutationassociatedwithshortqtsyndrome
AT stuartalang actionpotentialclampcharacterizationofthes631ahergmutationassociatedwithshortqtsyndrome
AT dempseychristophere actionpotentialclampcharacterizationofthes631ahergmutationassociatedwithshortqtsyndrome
AT hancoxjulesc actionpotentialclampcharacterizationofthes631ahergmutationassociatedwithshortqtsyndrome