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Initiation of Embryonic Cardiac Pacemaker Activity by Inositol 1,4,5-Trisphosphatedependent Calcium Signaling
Annabelle Méry *,
Franck Aimond *,
Claudine Ménard *,
Marek Michalak, and
Michel Pucéat *
* CRBM, Centre National de la Recherche Scientifique FRE2593, 34293 Montpellier, France RIKEN BSI, Saitama, IMSUT, University of Tokyo, Tokyo 108-8639, Japan
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
In the adult, the heart rate is driven by spontaneous and repetitivedepolarizations of pacemaker cells to generate a firing of actionpotentials propagating along the conduction system and spreadinginto the ventricles. In the early embryo before E9.5, the pacemakerionic channel responsible for the spontaneous depolarizationof cells is not yet functional. Thus the mechanisms that initiateearly heart rhythm during cardiogenesis are puzzling. In theabsence of a functional pacemaker ionic channel, the oscillatorynature of inositol 1,4,5-trisphosphate (InsP3)-induced intracellularCa2+ signaling could provide an alternative pacemaking mechanism.To test this hypothesis, we have engineered pacemaker cellsfrom embryonic stem (ES) cells, a model that faithfully recapitulatesearly stages of heart development. We show that InsP3-dependentshuttle of free Ca2+ in and out of the endoplasmic reticulumis essential for a proper generation of pacemaker activity duringearly cardiogenesis and fetal life.