ZFIN ID: ZDB-PUB-160429-11
Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression
Eden, M., Meder, B., Völkers, M., Poomvanicha, M., Domes, K., Branchereau, M., Marck, P., Will, R., Bernt, A., Rangrez, A., Busch, M., German Mouse Clinic Consortium, Hrabě de Angelis, M., Heymes, C., Rottbauer, W., Most, P., Hofmann, F., Frey, N.
Date: 2016
Source: Nature communications   7: 11317 (Journal)
Registered Authors: Meder, Benjamin
Keywords: Cell biology, Medical research
MeSH Terms:
  • Animals
  • Animals, Newborn
  • Calcium/metabolism*
  • Calcium Channels, L-Type/genetics*
  • Calcium Channels, L-Type/metabolism
  • Carrier Proteins/genetics*
  • Carrier Proteins/metabolism
  • Cells, Cultured
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Contraction/genetics
  • Myocardium/metabolism*
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/physiology
  • Protein Binding
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 27122098 Full text @ Nat. Commun.
FIGURES
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 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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