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.
Highlights
Calcium signalling plays a critical role in the pathogenesis of heart failure
On the basis of the notion that proteins expressed in the heart are likely to play a role in cardiac pathophysiology[23], we systematically screened the expressed sequence tag (EST) databases for sequences predominantly found in cardiac complementary DNA libraries[24]
ESTs in these clusters were significantly enriched in the heart compared with other tissues (Supplementary Fig. 1a) and are predicted to encode an open reading frame (ORF) termed FAM40B or STRIP2
Summary
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. Overexpression of Myoscape increases global Ca2 þ transients and enhances L-type Ca2 þ 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. Myoscape-deficient mice show reduced L-type Ca2 þ currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. The regulation of calcium fluxes occurs at the level of single channel activity and precise channel sublocalization within the plasma membrane[2] In cardiomyocytes, this microdomainconfined calcium influx controls the action potential duration and initiates calcium-induced calcium release and subsequent heart muscle contraction[3,4]. Myoscape ablation in cardiomyocytes in vitro or in zebrafish and in genetically engineered mice in vivo results in reduced contractility and progressive heart failure
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