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Mol. Biol. Cell 16 (5): 2414-2423

Copyright © 2005 by The American Society for Cell Biology.

Initiation of Embryonic Cardiac Pacemaker Activity by Inositol 1,4,5-Trisphosphate–dependent Calcium Signaling



Annabelle Méry *, Franck Aimond *, Claudine Ménard *, Katsuhiko Mikoshiba {dagger}, Marek Michalak {ddagger}, and Michel Pucéat *

* CRBM, Centre National de la Recherche Scientifique FRE2593, 34293 Montpellier, France
{dagger} RIKEN BSI, Saitama, IMSUT, University of Tokyo, Tokyo 108-8639, Japan {ddagger} Canadian Institutes for Health Research Membrane Protein Research Group and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Received for publication October 8, 2004. Revision received February 28, 2005. Accepted for publication March 1, 2005.

Monitoring Editor: Guido Guidotti

Abstract: In the adult, the heart rate is driven by spontaneous and repetitive depolarizations of pacemaker cells to generate a firing of action potentials propagating along the conduction system and spreading into the ventricles. In the early embryo before E9.5, the pacemaker ionic channel responsible for the spontaneous depolarization of cells is not yet functional. Thus the mechanisms that initiate early heart rhythm during cardiogenesis are puzzling. In the absence of a functional pacemaker ionic channel, the oscillatory nature of inositol 1,4,5-trisphosphate (InsP3)-induced intracellular Ca2+ signaling could provide an alternative pacemaking mechanism. To test this hypothesis, we have engineered pacemaker cells from embryonic stem (ES) cells, a model that faithfully recapitulates early stages of heart development. We show that InsP3-dependent shuttle of free Ca2+ in and out of the endoplasmic reticulum is essential for a proper generation of pacemaker activity during early cardiogenesis and fetal life.

This article was published online ahead of print in MBC in Press ( on March 9, 2005.



The online version of this article contains supplemental material at MBC Online (

Address correspondence to: M. Pucéat (michel.puceat{at}

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