Intracellular Ca2+ oscillations drive spontaneous contractions in cardiomyocytes during early development

Activity of cardiac pacemaker cells is caused by a balanced interplay of io n channels. However, it is not known how the rhythmic beating is initiated during early stages of cardiomyogenesis, when the expression of ion channel s is still incomplete. Based on the observation that early-stage embryonic stem cell-derived cardiomyocytes continuously contracted in high extracellu lar K+ solution, here we provide experimental evidence that the spontaneous activity of these cells is not generated by transmembrane ion currents, bu t by intracellular [Ca2+](i) oscillations. This early activity was clearly independent of voltage dependent L-type Ca2+ channels and the interplay bet ween these and ryanodine sensitive Ca2+ stores. We also show that intracell ular Ca2+ oscillations evoke small membrane depolarizations and that these can trigger L-type Ca2+ channel driven action potentials.