CARDIAC PACEMAKING Calcium Sets the Beat

Currents through the pacemaker channels in the membrane of sino-atrial pacemaker cells set the rhythm for cardiac action potentials, thereby driving the heartbeat. Mysteriously, though, the embryonic heart begins beating even before the pacemaker channel becomes functional. Méry et al. expressed enhanced yellow fluorescent protein under the transcriptional control of the isoform of myosin heavy-chain kinase (-MHCK) in cultured embryonic stem (ES) cell-derived cardiomyocytes (which form three-dimensional structures called embryoid bodies that contain cells with the different cardiac phenotypes) and thereby identified a population of pacemaker cells. The pacemaker cells showed spontaneous spikes in intracellular calcium concentration. In day 9 embryoid bodies, calcium spikes persisted after exposure to 140 mM KCl (to depolarize the cell and abolish the membrane potential) or in the presence of pharmacological blockers of the pacemaker channel, whereas at day 11 the blockers slowed, and 140 mM KCl abolished, calcium spikes. Overexpression in pacemaker cells of calreticulin, an endoplasmic reticulum (ER) calcium-binding protein, reduced embryoid body beating and calcium spikes, as did expression in pacemaker cells of antisense to the inositol 1,4,5-trisphosphate receptor (IP₃R). Expression of IP₃ phosphatase inhibited calcium spiking in pacemakers, as did microinjection of antibody to the type I IP₃R or exposure to an IP₃R inhibitor. Thus, the authors conclude that, early in embryogenesis, cardiac pacemaker activity depends on IP₃-dependent shuttling of calcium out of and into the ER.

A. Méry, F. Aimond, C. Ménard, K. Mikoshiba, M. Michalak, M. Pucéat, Initiation of embryonic cardiac pacemaker activity by inositol 1,4,5-trisphosphate-dependent calcium signaling. Mol. Biol. Cell 16, 2414-2423 (2005). [Abstract] [Full Text]