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Ca(2+) signaling in mouse cardiomyocytes with ablated S100A1 protein


Gusev, K; Ackermann, G E; Heizmann, C W; Niggli, E (2009). Ca(2+) signaling in mouse cardiomyocytes with ablated S100A1 protein. General Physiology and Biophysics, 28(4):371-383.

Abstract

S100A1 is a Ca(2+)-binding protein expressed at high levels in the myocardium. It is thought to modulate the Ca(2+) sensitivity of the sarcoplasmic reticulum (SR) Ca(2+) release channels (ryanodine receptors or RyRs) and its expression has been shown to be down regulated in various heart diseases. In this study we used S100A1 knock-out (KO) mice to investigate the consequences of chronic S100A1 deficiency on Ca(2+) cycling in ventricular cardiomyocytes. Confocal Ca(2+) imaging showed that field-stimulated KO myocytes had near normal Ca(2+) signaling under control conditions but a blunted response to beta-adrenergic stimulation with 1 micromol/l isoproterenol (ISO). Voltage-clamp experiments revealed that S100A1-deficient cardiomyocytes have elevated ICa under basal conditions. This larger Ca(2+) influx was accompanied by augmented Ca(2+) transients and elevated SR Ca(2+) content, without changes in macroscopic excitation-contraction coupling gain, which suggests impaired fractional Ca(2+) release. Exposure of KO and WT cells to ISO led to similar maximal I(Ca). Thus, the stimulation of the I(Ca) was less pronounced in KO cardiomyocytes, suggesting that changes in basal I(Ca) could underlie the reduced beta-adrenergic response. Taken together, our findings indicate that chronic absence of S100A1 results in enhanced L-type Ca(2+) channel activity combined with a blunted SR Ca(2+) release amplification. These findings may have implications in a variety of cardiac pathologies where abnormal RyR Ca(2+) sensitivity or reduced S100A1 levels have been described.

Abstract

S100A1 is a Ca(2+)-binding protein expressed at high levels in the myocardium. It is thought to modulate the Ca(2+) sensitivity of the sarcoplasmic reticulum (SR) Ca(2+) release channels (ryanodine receptors or RyRs) and its expression has been shown to be down regulated in various heart diseases. In this study we used S100A1 knock-out (KO) mice to investigate the consequences of chronic S100A1 deficiency on Ca(2+) cycling in ventricular cardiomyocytes. Confocal Ca(2+) imaging showed that field-stimulated KO myocytes had near normal Ca(2+) signaling under control conditions but a blunted response to beta-adrenergic stimulation with 1 micromol/l isoproterenol (ISO). Voltage-clamp experiments revealed that S100A1-deficient cardiomyocytes have elevated ICa under basal conditions. This larger Ca(2+) influx was accompanied by augmented Ca(2+) transients and elevated SR Ca(2+) content, without changes in macroscopic excitation-contraction coupling gain, which suggests impaired fractional Ca(2+) release. Exposure of KO and WT cells to ISO led to similar maximal I(Ca). Thus, the stimulation of the I(Ca) was less pronounced in KO cardiomyocytes, suggesting that changes in basal I(Ca) could underlie the reduced beta-adrenergic response. Taken together, our findings indicate that chronic absence of S100A1 results in enhanced L-type Ca(2+) channel activity combined with a blunted SR Ca(2+) release amplification. These findings may have implications in a variety of cardiac pathologies where abnormal RyR Ca(2+) sensitivity or reduced S100A1 levels have been described.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2009
Deposited On:03 Feb 2010 14:50
Last Modified:05 Apr 2016 13:50
Publisher:Slovenska Akademia Vied
ISSN:0231-5882
Publisher DOI:https://doi.org/10.4149/gpb_2009_04_371
PubMed ID:20097960

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