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Published on: January 18, 2019
Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein
Konstantin Gusev1, Gabriele E Ackermann, Claus W Heizmann
1Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland.
Insights
Chronic S100A1 deficiency in mice impairs cardiac calcium handling. S100A1-deficient heart cells show increased basal calcium influx but a reduced response to beta-adrenergic stimulation, impacting heart function.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Calcium Signaling
Background:
- S100A1 protein is abundant in the heart and regulates calcium sensitivity of ryanodine receptors.
- Reduced S100A1 expression is linked to various heart diseases.
- Understanding S100A1's role is crucial for cardiac pathology research.
Purpose of the Study:
- To investigate the effects of chronic S100A1 deficiency on calcium cycling in ventricular cardiomyocytes using S100A1 knock-out mice.
- To elucidate the functional consequences of S100A1 absence on cardiac excitation-contraction coupling.
Main Methods:
- Utilized S100A1 knock-out (KO) mouse models.
- Employed confocal calcium imaging to assess Ca2+ signaling.
- Performed voltage-clamp experiments to measure ionic currents (ICa) and sarcoplasmic reticulum (SR) Ca2+ content.
Main Results:
- S100A1-deficient cardiomyocytes exhibited elevated basal L-type calcium current (ICa) and increased SR Ca2+ content.
- KO myocytes showed blunted responses to beta-adrenergic stimulation (isoproterenol) compared to wild-type (WT).
- Impaired fractional Ca2+ release was suggested by normal excitation-contraction coupling gain despite augmented Ca2+ transients.
Conclusions:
- Chronic absence of S100A1 leads to enhanced basal L-type calcium channel activity.
- S100A1 deficiency results in blunted amplification of SR Ca2+ release upon beta-adrenergic stimulation.
- These findings highlight S100A1's critical role in normal cardiac function and suggest its involvement in heart diseases characterized by altered calcium handling.
Abstract:
S100A1 is a Ca2+-binding protein expressed at high levels in the myocardium. It is thought to modulate the Ca2+ sensitivity of the sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ cycling in ventricular cardiomyocytes. Confocal Ca2+ imaging showed that field-stimulated KO myocytes had near normal Ca2+ 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 Ca2+ influx was accompanied by augmented Ca2+ transients and elevated SR Ca2+ content, without changes in macroscopic excitation-contraction coupling gain, which suggests impaired fractional Ca2+ release. Exposure of KO and WT cells to ISO led to similar maximal ICa. Thus, the stimulation of the ICa was less pronounced in KO cardiomyocytes, suggesting that changes in basal ICa could underlie the reduced beta-adrenergic response. Taken together, our findings indicate that chronic absence of S100A1 results in enhanced L-type Ca2+ channel activity combined with a blunted SR Ca2+ release amplification. These findings may have implications in a variety of cardiac pathologies where abnormal RyR Ca2+ sensitivity or reduced S100A1 levels have been described.
