Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

• Verfasst von: Eden, Matthias [VerfasserIn]
• Verfasst von: Meder, Benjamin [VerfasserIn]
• Verfasst von: Völkers, Mirko [VerfasserIn]
• Verfasst von: Bekeredjian, Raffi [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Titel: Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression
• Verf.angabe: Matthias Eden, Benjamin Meder, Mirko Völkers, Montatip Poomvanicha, Katrin Domes, M. Branchereau, P. Marck, Rainer Will, Alexander Bernt, Ashraf Rangrez, Matthias Busch, German Mouse ClinicConsortiumw, Martin Hrabě de Angelis, Christophe Heymes, Wolfgang Rottbauer, Patrick Most, Franz Hofmann & Norbert Frey
• E-Jahr: 2016
• Jahr: 28 April 2016
• Umfang: 16 S.
• Fussnoten: Updated 26 May 2016 ; Gesehen am 13.06.2019 ; German Mouse Clinic Consortium: Thure Adler, Raffi Bekeredjian, Hugo Katus [und weitere]
• Titel Quelle: Enthalten in: Nature Communications
• Ort Quelle: [London] : Nature Publishing Group UK, 2010
• Jahr Quelle: 2016
• Band/Heft Quelle: 7(2016) Artikel-Nummer 11317, 16 Seiten
• ISSN Quelle: 2041-1723
• DOI: doi:10.1038/ncomms11317
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1667401769

Abstract

Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca2+ amplitudes and a lower diastolic Ca2+ content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca2+ transients and enhances L-type Ca2+ channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca2+currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease.