Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I–IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF). In spite of high homology, each of the iFGFs, iFGF11–iFGF14, as well as the individual iFGF splice variants, differentially regulates NaV channel gating, and the mechanisms underlying these differential effects remain elusive. Much of the work exploring iFGF regulation of NaV1.5 has been performed in mouse and rat ventricular myocytes in which iFGF13VY is the predominant iFGF expressed, whereas investigation into NaV1.5 regulation by the human heart-dominant iFGF12B is lacking. In this study, we used a mouse model with cardiac-specific Fgf13 deletion to study the consequences of iFGF13VY and iFGF12B expression. We observed distinct effects on the voltage-dependences of activation and inactivation of the sodium currents (INa), as well as on the kinetics of peak INa decay. Results in native myocytes were recapitulated with human NaV1.5 heterologously expressed in Xenopus oocytes, and additional experiments using voltage-clamp fluorometry (VCF) revealed iFGF-specific effects on the activation of the NaV1.5 voltage sensor domain in repeat IV (VSD-IV). iFGF chimeras further unveiled roles for all three iFGF domains (i.e., the N-terminus, core, and C-terminus) on the regulation of VSD-IV, and a slower time domain of inactivation. We present here a novel mechanism of iFGF regulation that is specific to individual iFGF isoforms and that leads to distinct functional effects on NaV channel/current kinetics.
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1 May 2023
Article|
March 21 2023
Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors
Paweorn Angsutararux
,
Paweorn Angsutararux
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
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Amal K. Dutta,
Amal K. Dutta
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
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Martina Marras
,
Martina Marras
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
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Carlota Abella,
Carlota Abella
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
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Rebecca L. Mellor
,
Rebecca L. Mellor
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
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Jingyi Shi,
Jingyi Shi
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
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Jeanne M. Nerbonne
,
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
3
Department of Developmental Biology, Washington University School of Medicine
, St. Louis, MO, USA
Jeanne M. Nerbonne: jnerbonne@wustl.edu
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Jonathan R. Silva
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
Correspondence to Jonathan R. Silva: jonsilva@wustl.edu
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Paweorn Angsutararux
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
Amal K. Dutta
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
Martina Marras
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
Carlota Abella
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
Rebecca L. Mellor
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
Jingyi Shi
1
Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
, St. Louis, MO, USA
2
Department of Medicine, Cardiovascular Division, Washington University School of Medicine
, St. Louis, MO, USA
3
Department of Developmental Biology, Washington University School of Medicine
, St. Louis, MO, USA
Correspondence to Jonathan R. Silva: jonsilva@wustl.edu
Jeanne M. Nerbonne: jnerbonne@wustl.edu
This work is part of a special issue on Structure and Function of Ion Channels in Native Cells and Macromolecular Complexes.
Received:
November 14 2022
Revision Received:
January 17 2023
Accepted:
February 09 2023
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
National Heart, Lung, and Blood Institute
Funder(s):
National Institutes of Health
- Award Id(s): R01 142520,R01 HL150637
Funder(s):
National Center for Research Resources
- Award Id(s): UL1 RR024992
Funder(s):
Institute for Clinical and Translational Sciences at Washington University
Funder(s):
Hope Center for Neurological Disorders
- Award Id(s): P30 NS057105
© 2023 Angsutararux et al.
2023
Angsutararux et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2023) 155 (5): e202213300.
Article history
Received:
November 14 2022
Revision Received:
January 17 2023
Accepted:
February 09 2023
Citation
Paweorn Angsutararux, Amal K. Dutta, Martina Marras, Carlota Abella, Rebecca L. Mellor, Jingyi Shi, Jeanne M. Nerbonne, Jonathan R. Silva; Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors. J Gen Physiol 1 May 2023; 155 (5): e202213300. doi: https://doi.org/10.1085/jgp.202213300
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