Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein.
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.
Gusev
Konstantin
K
Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland.
Ackermann
Gabriele E
GE
Heizmann
Claus W
CW
Niggli
Ernst
E
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D004553:Electric Conductivity; D005260:Female; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins / Q000172:deficiency* / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D002118:Calcium