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Rinné, Susanne; Kiper, Aytug K.; Jacob, Ralf; Ortiz-Bonnin, Beatriz; Schindler, Roland F.R.; Fischer, Sabine; Komadowski, Marlene; De Martino, Emilia; Schäfer, Martin K.-H.; Cornelius, Tamina; Fabritz, Larissa; Helker, Christian S.M.; Brand, Thomas; Decher, Niels
iScience, 05/2024, Volume: 27, Issue: 5Journal Article
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. Display omitted •Popeye-domain-containing proteins (POPDC) modulate the cardiac sodium channel Nav1.5•POPDC2 modulates Nav1.5 surface expression and currents in a cAMP-dependent manner•Knock-down of popdc2 in embryonic zebrafish indicate altered sodium channel densities•Nav1.5 modulation might be relevant for sympathetic stimulation and arrhythmias Biochemistry; Molecular biology; Physiology
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