Calcium handling in embryonic stem cell-derived cardiac myocytes: of mice and men.
Excitation-contraction (EC) coupling is fundamental to the function of cardiac myocytes (CMs). In mature myocytes plasma membrane (PM) L-type Ca(2+) channels function in close juxtaposition to ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) membrane. Action potentials (APs) cause the opening of PM L-type Ca(2+) channels, which in turn provide trigger Ca(2+) for a larger RyR-mediated SR Ca(2+) release. In contrast, developing myocytes have a less well-developed SR. This incomplete development is observed in early stage and mid-maturation stages of murine embryonic stem cell-derived cardiac myocytes (ESC-CMs). Despite the absence of a well-developed t-tubule system, murine ESC-CMs use internal Ca(2+) stores for EC coupling. Direct measures of Ca(2+) handling, including pharmacological studies and investigation of genetically modified mouse ESC-CMs, established an important contribution of RyR-mediated internal Ca(2+) store to cell function. Similarly, early-stage human ESC-CMs use internal Ca(2+) store and partially share Ca(2+) handling characteristics with murine ESC-CMs. For example, elementary Ca(2+) release events are present in both murine and human ESC-CMs, and it is likely that Ca(2+) handling contributes to automatic rhythm generation in these cells. However, in human ESC-CMs, a unique voltage-gated Na(+) channel window current is critical for spontaneous, rhythmic depolarization. The advent of the murine and human ES cardiomyocyte differentiating systems has provided initial insights into the early steps of development of excitability and electromechanical coupling in the mammalian heart, including patterns of gene expression, myofibrillogenesis, ion channel development and function, and Ca(2+) handling. Here we discuss the information gained from these models to describe the nexus of voltage-gated channel currents and Ca(2+) handling on rhythmic activity.
Itzhaki
Ilanit
I
Department of Physiology, The Bruce Rappaport Institute in the Medical Sciences, Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 32000, Israel.
Schiller
Jackie
J
Beyar
Rafael
R
Satin
Jonathan
J
Gepstein
Lior
L
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*
D002118:Calcium