Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5

Susanne Rinné; Aytug K. Kiper; Ralf Jacob; Beatriz Ortiz-Bonnin; Roland F.R. Schindler; Sabine Fischer; Marlene Komadowski; Emilia deMartino; Martin K -H Schafer; Tamina Cornelius; Larissa Fabritz; Christian S.M. Helker; Thomas Brand; Niels Decher

doi:10.1016/j.isci.2024.109696

Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5

Susanne Rinné, Aytug K. Kiper, Ralf Jacob, Beatriz Ortiz-Bonnin, Roland F.R. Schindler, Sabine Fischer, Marlene Komadowski, Emilia deMartino, Martin K -H Schafer, Tamina Cornelius, Larissa Fabritz, Christian S.M. Helker, Thomas Brand, Niels Decher^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Popeye-domain-containing proteins (POPDC) are predominantly expressed in the heart and skeletal muscle, modulating the K_2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.

Original language	English
Article number	109696
Journal	iScience
Early online date	9 Apr 2024
DOIs	https://doi.org/10.1016/j.isci.2024.109696
Publication status	E-pub ahead of print - 9 Apr 2024

Bibliographical note

Acknowledgments:
This work was supported by a grant of the Universitätsklinikum Gießen und Marburg to S.R. and A.K.K.. Funding: European Union (grant agreement No 965286 [MAESTRIA] to LF). Work in the Brand lab was funded by the British Heart Foundation (PG/14/46/30911, PG/14/83/31128). N.D. is supported by Deutsche Forschungsgemeinschaft (DFG) grant DE1482-9/1. We thank Ursula Herbort-Brand and Simone Preis for expert technical assistance.

Keywords

ion channel
Nav1.5
POPDCP
Popeye-domain-containing proteins
SCN5A
sodium channel

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Rinné, S., Kiper, A. K., Jacob, R., Ortiz-Bonnin, B., Schindler, R. F. R., Fischer, S., Komadowski, M., deMartino, E., Schafer, M. K. .-H., Cornelius, T., Fabritz, L., Helker, C. S. M., Brand, T., & Decher, N. (2024). Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5. iScience, Article 109696. Advance online publication. https://doi.org/10.1016/j.isci.2024.109696

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title = "Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5",

abstract = "Popeye-domain-containing proteins (POPDC) are predominantly expressed in the heart and skeletal muscle, modulating the K2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.",

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author = "Susanne Rinn{\'e} and Kiper, {Aytug K.} and Ralf Jacob and Beatriz Ortiz-Bonnin and Schindler, {Roland F.R.} and Sabine Fischer and Marlene Komadowski and Emilia deMartino and Schafer, {Martin K -H} and Tamina Cornelius and Larissa Fabritz and Helker, {Christian S.M.} and Thomas Brand and Niels Decher",

note = "Acknowledgments: This work was supported by a grant of the Universit{\"a}tsklinikum Gie{\ss}en und Marburg to S.R. and A.K.K.. Funding: European Union (grant agreement No 965286 [MAESTRIA] to LF). Work in the Brand lab was funded by the British Heart Foundation (PG/14/46/30911, PG/14/83/31128). N.D. is supported by Deutsche Forschungsgemeinschaft (DFG) grant DE1482-9/1. We thank Ursula Herbort-Brand and Simone Preis for expert technical assistance. ",

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AU - Rinné, Susanne

AU - Kiper, Aytug K.

AU - Jacob, Ralf

AU - Ortiz-Bonnin, Beatriz

AU - Schindler, Roland F.R.

AU - Fischer, Sabine

AU - Komadowski, Marlene

AU - deMartino, Emilia

AU - Schafer, Martin K -H

AU - Cornelius, Tamina

AU - Fabritz, Larissa

AU - Helker, Christian S.M.

AU - Brand, Thomas

AU - Decher, Niels

N1 - Acknowledgments: This work was supported by a grant of the Universitätsklinikum Gießen und Marburg to S.R. and A.K.K.. Funding: European Union (grant agreement No 965286 [MAESTRIA] to LF). Work in the Brand lab was funded by the British Heart Foundation (PG/14/46/30911, PG/14/83/31128). N.D. is supported by Deutsche Forschungsgemeinschaft (DFG) grant DE1482-9/1. We thank Ursula Herbort-Brand and Simone Preis for expert technical assistance.

PY - 2024/4/9

Y1 - 2024/4/9

N2 - Popeye-domain-containing proteins (POPDC) are predominantly expressed in the heart and skeletal muscle, modulating the K2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.

AB - Popeye-domain-containing proteins (POPDC) are predominantly expressed in the heart and skeletal muscle, modulating the K2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.

KW - ion channel

KW - Nav1.5

KW - POPDCP

KW - Popeye-domain-containing proteins

KW - SCN5A

KW - sodium channel

U2 - 10.1016/j.isci.2024.109696

DO - 10.1016/j.isci.2024.109696

M3 - Article

SN - 2589-0042

JO - iScience

JF - iScience

M1 - 109696

ER -

Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5

Abstract

Bibliographical note

Keywords

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