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

Annabelle Méry ^*, Franck Aimond ^*, Claudine Ménard ^*, Katsuhiko Mikoshiba , 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

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.

Address correspondence to: M. Pucéat (michel.puceat{at}crbm.cnrs.fr).

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