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β1 and β3 subunits amplify mechanosensitivity of the cardiac voltage-gated sodium channel Nav1.5

  • Ion channels, receptors and transporters
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Abstract

In cardiomyocytes, electrical activity is coupled to cellular contraction, thus exposing all proteins expressed in the sarcolemma to mechanical stress. The voltage-gated sodium channel Nav1.5 is the main contributor to the rising phase of the action potential in the heart. There is growing evidence that gating and kinetics of Nav1.5 are modulated by mechanical forces and pathogenic variants that affect mechanosensitivity have been linked to arrhythmias. Recently, the sodium channel β1 subunit has been described to stabilise gating against mechanical stress of Nav1.7 expressed in neurons. Here, we tested the effect of β1 and β3 subunits on mechanosensitivity of the cardiac Nav1.5. β1 amplifies stress-induced shifts of V1/2 of steady-state fast inactivation to hyperpolarised potentials (ΔV1/2: 6.2 mV without and 10.7 mV with β1 co-expression). β3, on the other hand, almost doubles stress-induced speeding of time to sodium current transient peak (Δtime to peak at − 30 mV: 0.19 ms without and 0.37 ms with β3 co-expression). Our findings may indicate that in cardiomyocytes, the interdependence of electrical activity and contraction is used as a means of fine tuning cardiac sodium channel function, allowing quicker but more strongly inactivating sodium currents under conditions of increased mechanical stress. This regulation may help to shorten action potential duration during tachycardia, to prevent re-entry phenomena and thus arrhythmias.

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Data availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Daniela Graef, Brigitte Hoch, and Petra Hautvast for the excellent technical support, Martin Hampl for the advice on analysis of patch clamp data and Professor Christian Alzheimer and PD Tobias Huth for the use of laboratory facilities.

Funding

None of the mentioned funding sources were involved in the study design, data collection and analysis, interpretation of the data, writing the paper or decision to submit the paper for publication.

This work was supported by the Interdisciplinary Center for Clinical Research (University Hospital Erlangen, IZKF projects E25 and Junior Project J66 and rotation fellowship to EE) the German Federal Ministry of Education and Research (BMBF 01EK1609A), the German Research Foundation (DFG RTG 2162, RTG 2416, LA 2740/3-1), the Bavarian Ministry of Science, and the Arts in the framework of ForInter.

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Authors and Affiliations

  1. Department of Anaesthesiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany

    Michele Maroni, Jürgen Schüttler & Esther Eberhardt

  2. Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany

    Michele Maroni & Beate Winner

  3. Institute of Physiology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

    Jannis Körner & Angelika Lampert

  4. Department of Anaesthesiology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

    Jannis Körner

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  1. Michele Maroni
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Contributions

MM: performed patch-clamp experiments, analysed and interpreted the data, contributed to the manuscript

JK: performed homology modelling, analysed, interpreted and discussed the data, reviewed the manuscript

JS: conceived the study, reviewed the manuscript

BW: conceived the study, discussed the data, reviewed the manuscript

AL: conceived the study, interpreted and discussed the data, reviewed the manuscript

EE: conceived the study, planned experiments, analysed and interpreted the data, wrote the manuscript

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Correspondence to Esther Eberhardt.

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Maroni, M., Körner, J., Schüttler, J. et al. β1 and β3 subunits amplify mechanosensitivity of the cardiac voltage-gated sodium channel Nav1.5. Pflugers Arch - Eur J Physiol 471, 1481–1492 (2019). https://doi.org/10.1007/s00424-019-02324-w

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