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J. Biol. Chem., Vol. 280, Issue 43, 36019-36028, October 28, 2005

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S100A1 Enhances the L-type Ca²⁺ Current in Embryonic Mouse and Neonatal Rat Ventricular Cardiomyocytes^*

Michael Reppel1, Philipp Sasse, Roland Piekorz¶, Ming Tang||, Wilhelm Roell**, Yaqi Duan, Anja Kletke¶, Jürgen Hescheler, Bernd Nürnberg¶, and Bernd K. Fleischmann2

From the Institute of Neurophysiology, University of Cologne, Cologne 50931, Germany, Institute of Physiology I and ^**Department of Cardiothoracic Surgery, University of Bonn, Bonn 53105, Germany, the ^¶Department of Biochemistry and Molecular Biology II, University of Düsseldorf, 40225 Düsseldorf, Germany, and the ^||Department of Physiology, Tongji Medical College, Wuhan 4-30030, China

S100A1 is an EF-hand type Ca²⁺-binding protein with a muscle-specific expression pattern. The highest S100A1 protein levels are found in cardiomyocytes, and it is expressed already at day 8 in the heart during embryonic development. Since S100A1 is known to be involved in the regulation of Ca²⁺ homeostasis, we tested whether extracellular S100A1 plays a role in regulating the L-type Ca²⁺ current (I_Ca) in ventricular cardiomyocytes. Murine embryonic (day 16.5 postcoitum) ventricular cardiomyocytes were incubated with S100A1 (0.001–10 µM) for different time periods (20 min to 48 h). I_Ca density was found to be significantly increased as early as 20 min (from –10.8 ± 1 pA/pF, n = 18, to –22.9 ± 1.4 pA/pF; +112.5 ± 13%, n = 9, p < 0.001) after the addition of S100A1 (1 µM). S100A1 also enhanced I_Ca current density in neonatal rat cardiomyocytes. Fluorescence and capacitance measurements evidenced a fast translocation of rhodamine-coupled S100A1 from the extracellular space into cardiomyocytes. S100A1 treatment did not affect cAMP levels. However, protein kinase inhibitor, a blocker of cAMP-dependent protein kinase A (PKA), abolished the S100A1-induced enhancement of I_Ca. Accordingly, measurements of PKA activity yielded a significant increase in S100A1-treated cardiomyocytes. In vitro reconstitution assays further demonstrated that S100A1 enhanced PKA activity. We conclude that the Ca²⁺-binding protein S100A1 augments transsarcolemmal Ca²⁺ influx via an increase of PKA activity in ventricular cardiomyocytes and hence represents an important regulator of cardiac function.

Received for publication, April 29, 2005 , and in revised form, August 18, 2005.

^* This study was supported by grants of the Deutsche Gesellschaft für Kardiologie (to M. R.) and by the Deutsche Forschungsgemeinschaft (to B. N. and R. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Institute of Neurophysiology, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany. Tel.: 49-478-6966; Fax: 49-221-3834; E-mail: michael.reppel{at}uni-koeln.de. ² To whom correspondence may be addressed: Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel.: 49-228-6885-200; Fax: 49-228-6885-201; E-mail: bernd.fleischmann{at}uni-bonn.de.

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