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Local Control of Excitation-Contraction Coupling in Human Embryonic Stem Cell-Derived Cardiomyocytes

By Wei-Zhong Zhu, Luis F. Santana and Michael A. Laflamme


We investigated the mechanisms of excitation-contraction (EC) coupling in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and fetal ventricular myocytes (hFVMs) using patch-clamp electrophysiology and confocal microscopy. We tested the hypothesis that Ca2+ influx via voltage-gated L-type Ca2+ channels activates Ca2+ release from the sarcoplasmic reticulum (SR) via a local control mechanism in hESC-CMs and hFVMs. Field-stimulated, whole-cell [Ca2+]i transients in hESC-CMs required Ca2+ entry through L-type Ca2+ channels, as evidenced by the elimination of such transients by either removal of extracellular Ca2+ or treatment with diltiazem, an L-type channel inhibitor. Ca2+ release from the SR also contributes to the [Ca2+]i transient in these cells, as evidenced by studies with drugs interfering with either SR Ca2+ release (i.e. ryanodine and caffeine) or reuptake (i.e. thapsigargin and cyclopiazonic acid). As in adult ventricular myocytes, membrane depolarization evoked large L-type Ca2+ currents (ICa) and corresponding whole-cell [Ca2+]i transients in hESC-CMs and hFVMs, and the amplitude of both ICa and the [Ca2+]i transients were finely graded by the magnitude of the depolarization. hESC-CMs exhibit a decreasing EC coupling gain with depolarization to more positive test potentials, “tail” [Ca2+]i transients upon repolarization from extremely positive test potentials, and co-localized ryanodine and sarcolemmal L-type Ca2+ channels, all findings that are consistent with the local control hypothesis. Finally, we recorded Ca2+ sparks in hESC-CMs and hFVMs. Collectively, these data support a model in which tight, local control of SR Ca2+ release by the ICa during EC coupling develops early in human cardiomyocytes

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  3. (2001). Excitation-contraction coupling and cardiac contractile force.
  4. (2008). Calcium sparks.
  5. (1995). The control of calcium release in heart muscle.
  6. (1993). Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle.
  7. (1990). Voltage-independent calcium release in heart muscle.
  8. (1992). Theory of excitation-contraction coupling in cardiac muscle.
  9. (1994). Local control of excitation-contraction coupling in rat heart cells.
  10. (1979). Use of chlorotetracycline fluorescence to demonstrate Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum of skinned cardiac cells.
  11. (1995). Local calcium transients triggered by single L-type calcium channel currents in cardiac cells.
  12. (1996). Relation between the sarcolemmal Ca2+ current and Ca2+ sparks and local control theories for cardiac excitation-contraction coupling.
  13. (1994). Processes that remove calcium from the cytoplasm during excitation-contraction coupling in intact rat heart cells.
  14. (2006). Calcium flux in turtle ventricular myocytes.
  15. (1983). Rapid photochemical inactivation of Ca2+-antagonists shows that Ca2+ entry directly activates contraction in frog heart.
  16. (1992). Modulation of contraction by intracellular Na+ via Na(+)-Ca2+ exchange in single shark (Squalus acanthias) ventricular myocytes.
  17. (2002). Developmental changes of Ca(2+) handling in mouse ventricular cells from early embryo to adulthood.
  18. (2000). Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release.
  19. (1999). Intracellular Ca2+ oscillations drive spontaneous contractions in cardiomyocytes during early development.
  20. (2006). Diversity of Ca2+ signaling in developing cardiac cells.
  21. (2007). Intracellular Ca2+ oscillations, a potential pacemaking mechanism in early embryonic heart cells.
  22. (1998). Embryonic stem cell lines derived from human blastocysts.
  23. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts.
  24. (2001). Feeder-free growth of undifferentiated human embryonic stem cells.
  25. (2001). Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure.
  26. (2002). Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes.
  27. (1999). Amplitude distribution of calcium sparks in confocal images: theory and studies with an automatic detection method.
  28. (1997). Calcium sparks and excitationcontraction coupling in phospholamban-deficient mouse ventricular myocytes.
  29. (1999). G(s) and adenylyl cyclase in transverse tubules of heart: implications for cAMP-dependent signaling.
  30. (2003). Cellular basis of abnormal calcium transients of failing human ventricular myocytes.
  31. (1987). Effect of membrane potential changes on the calcium transient in single rat cardiac muscle cells.
  32. (1989). Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes.
  33. (1997). Amount of calcium in the sarcoplasmic reticulum: influence on excitation-contraction coupling in heart muscle.
  34. (1988). Mechanism of release of calcium from sarcoplasmic reticulum of guinea-pig cardiac cells.
  35. (1991). Role of Ca2+ channel in cardiac excitationcontraction coupling in the rat: evidence from Ca2+ transients and contraction.
  36. (1983). Calcium transients studied under voltageclamp control in frog twitch muscle fibres.
  37. (2001). Dynamic regulation of sarcoplasmic reticulum Ca(2+) content and release by luminal Ca(2+)-sensitive leak in rat ventricular myocytes.
  38. (1999). Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles.
  39. (1997). Numerical analysis of ryanodine receptor activation by L-type channel activity in the cardiac muscle diad.
  40. (1992). Macroscopic and unitary properties of physiological ion flux through L-type Ca2+ channels in guinea-pig heart cells.
  41. (1997). Numerical simulation of local calcium movements during L-type calcium channel gating in the cardiac diad.
  42. (2006). Calcium handling in embryonic stem cell-derived cardiac myocytes: of mice and men.
  43. (2001). Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes.
  44. (2007). Functional Sarcoplasmic Reticulum for Calcium-Handling of Human Embryonic Stem Cell-Derived Cardiomyocytes: Insights for Driven Maturation. Stem Cells.
  45. (2003). Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells.
  46. (2006). Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction.
  47. (2008). Calcium handling in human embryonic stem cell-derived cardiomyocytes.
  48. (2005). Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures.
  49. (1997). Increased expression of the cardiac L-type calcium channel in estrogen receptordeficient mice.
  50. (1996). Differences in isoproterenol stimulation of Ca2+ current of rat ventricular myocytes in neonatal compared to adult.
  51. (1998). Transmural heterogeneity of action potentials and Ito1 in myocytes isolated from the human right ventricle.
  52. (2004). Developmental changes of intracellular Ca2+ transients in beating rat hearts.
  53. (1989). Effect of ryanodine on neonatal and adult rat heart: developmental increase in sarcoplasmic reticulum function.
  54. (1999). Subcellular [Ca2+]i gradients during excitation-contraction coupling in newborn rabbit ventricular myocytes.
  55. (2008). Ontogeny of Ca2+-induced Ca2+ release in rabbit ventricular myocytes.
  56. (1999). Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium.
  57. (2006). Mechanisms underlying variations in excitation-contraction coupling across the mouse left ventricular free wall.
  58. (2007). Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach.
  59. (2003). Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization.

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