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

Nat. Commun. 7:11317 (2016)
Publishers Version Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
as soon as is submitted to ZB.
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 Ca(2+) amplitudes and a lower diastolic Ca(2+) 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 Ca(2+) transients and enhances L-type Ca(2+) 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 Ca(2+)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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calmodulin Kinase-ii; Ca2+ Channel; Dilated Cardiomyopathy; Heart-failure; Ventricular Myocytes; Failing Human; Adrenergic Regulation; Protein Stability; Ca(v)1.2 Channel; Embryonic Heart
Reviewing status