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 De Martino; Martin K-H Schäfer; 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

iScience. 2024 Apr 9;27(5):109696. doi: 10.1016/j.isci.2024.109696. eCollection 2024 May 17.

Authors

Affiliations

¹ Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany.
² Institute of Cytobiology, Center for Synthetic Microbiology, Philipps-University of Marburg, 35043 Marburg, Germany.
³ National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK.
⁴ Faculty of Biology, Cell Signaling and Dynamics, Philipps-University Marburg, 35043 Marburg, Germany.
⁵ Institute of Anatomy and Cell Biology, Philipps-University of Marburg, 35037 Marburg, Germany.
⁶ Institute of Cardiovascular Sciences University of Birmingham, Birmingham B15 2TT, UK.
⁷ University Center of Cardiovascular Sciences & Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg Eppendorf, 20251 Hamburg and DZHK Hamburg/Kiel/Lübeck, Germany.

Abstract

Popeye domain containing (POPDC) proteins 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.

Keywords: Biochemistry; Molecular biology; Physiology.