Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Aytug K. Kiper
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Ralf Jacob
Institute of Cytobiology, Center for Synthetic Microbiology, Philipps-University of Marburg, 35043 Marburg, Germany
Beatriz Ortiz-Bonnin
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Roland F.R. Schindler
National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK
Sabine Fischer
Faculty of Biology, Cell Signaling and Dynamics, Philipps-University Marburg, 35043 Marburg, Germany
Marlene Komadowski
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Emilia De Martino
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Martin K.-H. Schäfer
Institute of Anatomy and Cell Biology, Philipps-University of Marburg, 35037 Marburg, Germany
Tamina Cornelius
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany
Larissa Fabritz
Institute of Cardiovascular Sciences University of Birmingham, Birmingham B15 2TT, UK; 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
Christian S.M. Helker
Faculty of Biology, Cell Signaling and Dynamics, Philipps-University Marburg, 35043 Marburg, Germany
Thomas Brand
National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK
Niels Decher
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 30537 Marburg, Germany; Corresponding author
Summary: Popeye domain containing (POPDC) proteins 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.
