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

  • Michele Maroni
  • Jannis Körner
  • Jürgen Schüttler
  • Beate Winner
  • Angelika Lampert
  • Esther EberhardtEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters

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.

Keywords

Sodium channel Mechanosensitivity Patch-clamp Cardiac ion channel 

Notes

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.

Author contribution

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

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

424_2019_2324_MOESM1_ESM.docx (288 kb)
ESM 1 (DOCX 287 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnaesthesiologyFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)ErlangenGermany
  2. 2.Department of Stem Cell BiologyFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)ErlangenGermany
  3. 3.Institute of Physiology, Medical FacultyRWTH Aachen UniversityAachenGermany
  4. 4.Department of Anaesthesiology, Medical FacultyRWTH Aachen UniversityAachenGermany

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