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. 2001 Jan;80(1):1–11. doi: 10.1016/S0006-3495(01)75991-7

Underlying mechanisms of symmetric calcium wave propagation in rat ventricular myocytes.

S Subramanian 1, S Viatchenko-Karpinski 1, V Lukyanenko 1, S Györke 1, T F Wiesner 1
PMCID: PMC1301210  PMID: 11159379

Abstract

Calcium waves in heart cells are mediated by diffusion-coupled calcium-induced calcium release. The waves propagate in circular fashion. This is counterintuitive in view of the accepted ultrastructure of the cardiac myocyte. The density of calcium release sites in the transverse direction is four times higher than in the longitudinal direction. Simulations with release sites localized along Z-lines and isotropic diffusion yielded highly elliptical, nonphysiological waves. We hypothesized that subcellular organelles counteracted the higher release site density along the Z-lines by acting as transverse diffusion barriers and sites of active calcium uptake. We quantified the reduction of transverse diffusion by microinjecting cells with the nonreactive dye fluorescein. The ratio of the radial diffusion coefficient to the longitudinal coefficient was 0.39. Inhibition of mitochondrial uptake by rotenone accelerated the wave in the transverse direction. Simulations with release sites clustered at the Z-lines and a transverse diffusion coefficient 50% of the longitudinal coefficient generated waves of ellipticity 2/1 (major axis along the Z-line). Introducing additional release sites between the Z-lines at a density 20% of that on the Z-lines produced circular waves. The experiments and simulations support the presence of transverse diffusion barriers, additional uptake sites, and possibly intermediate release sites as well.

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Selected References

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  1. Allbritton N. L., Meyer T., Stryer L. Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science. 1992 Dec 11;258(5089):1812–1815. doi: 10.1126/science.1465619. [DOI] [PubMed] [Google Scholar]
  2. Balke C. W., Egan T. M., Wier W. G. Processes that remove calcium from the cytoplasm during excitation-contraction coupling in intact rat heart cells. J Physiol. 1994 Feb 1;474(3):447–462. doi: 10.1113/jphysiol.1994.sp020036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bassani R. A., Bassani J. W., Bers D. M. Relaxation in ferret ventricular myocytes: unusual interplay among calcium transport systems. J Physiol. 1994 Apr 15;476(2):295–308. doi: 10.1113/jphysiol.1994.sp020131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bugrim A. E., Zhabotinsky A. M., Epstein I. R. Calcium waves in a model with a random spatially discrete distribution of Ca2+ release sites. Biophys J. 1997 Dec;73(6):2897–2906. doi: 10.1016/S0006-3495(97)78318-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cheng H., Cannell M. B., Lederer W. J. Propagation of excitation-contraction coupling into ventricular myocytes. Pflugers Arch. 1994 Oct;428(3-4):415–417. doi: 10.1007/BF00724526. [DOI] [PubMed] [Google Scholar]
  6. Cheng H., Lederer M. R., Lederer W. J., Cannell M. B. Calcium sparks and [Ca2+]i waves in cardiac myocytes. Am J Physiol. 1996 Jan;270(1 Pt 1):C148–C159. doi: 10.1152/ajpcell.1996.270.1.C148. [DOI] [PubMed] [Google Scholar]
  7. Cheng H., Lederer M. R., Xiao R. P., Gómez A. M., Zhou Y. Y., Ziman B., Spurgeon H., Lakatta E. G., Lederer W. J. Excitation-contraction coupling in heart: new insights from Ca2+ sparks. Cell Calcium. 1996 Aug;20(2):129–140. doi: 10.1016/s0143-4160(96)90102-5. [DOI] [PubMed] [Google Scholar]
  8. Dawson S. P., Keizer J., Pearson J. E. Fire-diffuse-fire model of dynamics of intracellular calcium waves. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6060–6063. doi: 10.1073/pnas.96.11.6060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duchen M. R., Leyssens A., Crompton M. Transient mitochondrial depolarizations reflect focal sarcoplasmic reticular calcium release in single rat cardiomyocytes. J Cell Biol. 1998 Aug 24;142(4):975–988. doi: 10.1083/jcb.142.4.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Engel J., Fechner M., Sowerby A. J., Finch S. A., Stier A. Anisotropic propagation of Ca2+ waves in isolated cardiomyocytes. Biophys J. 1994 Jun;66(6):1756–1762. doi: 10.1016/S0006-3495(94)80997-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Engel J., Sowerby A. J., Finch S. A., Fechner M., Stier A. Temperature dependence of Ca2+ wave properties in cardiomyocytes: implications for the mechanism of autocatalytic Ca2+ release in wave propagation. Biophys J. 1995 Jan;68(1):40–45. doi: 10.1016/S0006-3495(95)80196-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Escobar A. L., Cifuentes F., Vergara J. L. Detection of Ca(2+)-transients elicited by flash photolysis of DM-nitrophen with a fast calcium indicator. FEBS Lett. 1995 May 15;364(3):335–338. doi: 10.1016/0014-5793(95)00425-9. [DOI] [PubMed] [Google Scholar]
  13. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol. 1983 Jul;245(1):C1–14. doi: 10.1152/ajpcell.1983.245.1.C1. [DOI] [PubMed] [Google Scholar]
  14. Failli P., Ruocco C., Fazzini A., Giotti A. Calcium waves in unstimulated left ventricular cardiomyocytes isolated from aged spontaneously hypertensive and normotensive rats. Biochem Biophys Res Commun. 1997 Aug 8;237(1):103–106. doi: 10.1006/bbrc.1997.7079. [DOI] [PubMed] [Google Scholar]
  15. Forbes M. S., van Neil E. E. Membrane systems of guinea pig myocardium: ultrastructure and morphometric studies. Anat Rec. 1988 Dec;222(4):362–379. doi: 10.1002/ar.1092220409. [DOI] [PubMed] [Google Scholar]
  16. Franzini-Armstrong C. Functional significance of membrane architecture in skeletal and cardiac muscle. Soc Gen Physiol Ser. 1996;51:3–18. [PubMed] [Google Scholar]
  17. Franzini-Armstrong C., Protasi F., Ramesh V. Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles. Biophys J. 1999 Sep;77(3):1528–1539. doi: 10.1016/S0006-3495(99)77000-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Franzini-Armstrong C., Protasi F. Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. Physiol Rev. 1997 Jul;77(3):699–729. doi: 10.1152/physrev.1997.77.3.699. [DOI] [PubMed] [Google Scholar]
  19. Grouselle M., Stuyvers B., Bonoron-Adele S., Besse P., Georgescauld D. Digital-imaging microscopy analysis of calcium release from sarcoplasmic reticulum in single rat cardiac myocytes. Pflugers Arch. 1991 Mar;418(1-2):109–119. doi: 10.1007/BF00370459. [DOI] [PubMed] [Google Scholar]
  20. Gunter T. E., Gunter K. K., Sheu S. S., Gavin C. E. Mitochondrial calcium transport: physiological and pathological relevance. Am J Physiol. 1994 Aug;267(2 Pt 1):C313–C339. doi: 10.1152/ajpcell.1994.267.2.C313. [DOI] [PubMed] [Google Scholar]
  21. Gunter T. E., Pfeiffer D. R. Mechanisms by which mitochondria transport calcium. Am J Physiol. 1990 May;258(5 Pt 1):C755–C786. doi: 10.1152/ajpcell.1990.258.5.C755. [DOI] [PubMed] [Google Scholar]
  22. Györke S., Lukyanenko V., Györke I. Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes. J Physiol. 1997 Apr 15;500(Pt 2):297–309. doi: 10.1113/jphysiol.1997.sp022021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  24. Harkins A. B., Kurebayashi N., Baylor S. M. Resting myoplasmic free calcium in frog skeletal muscle fibers estimated with fluo-3. Biophys J. 1993 Aug;65(2):865–881. doi: 10.1016/S0006-3495(93)81112-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ishide N., Urayama T., Inoue K., Komaru T., Takishima T. Propagation and collision characteristics of calcium waves in rat myocytes. Am J Physiol. 1990 Sep;259(3 Pt 2):H940–H950. doi: 10.1152/ajpheart.1990.259.3.H940. [DOI] [PubMed] [Google Scholar]
  26. Izu L. T., Wier W. G., Balke C. W. Theoretical analysis of the Ca2+ spark amplitude distribution. Biophys J. 1998 Sep;75(3):1144–1162. doi: 10.1016/s0006-3495(98)74034-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Jaffe L. F. The path of calcium in cytosolic calcium oscillations: a unifying hypothesis. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9883–9887. doi: 10.1073/pnas.88.21.9883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jorgensen A. O., Shen A. C., Arnold W., McPherson P. S., Campbell K. P. The Ca2+-release channel/ryanodine receptor is localized in junctional and corbular sarcoplasmic reticulum in cardiac muscle. J Cell Biol. 1993 Feb;120(4):969–980. doi: 10.1083/jcb.120.4.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jorgensen A. O., Shen A. C., Campbell K. P. Ultrastructural localization of calsequestrin in adult rat atrial and ventricular muscle cells. J Cell Biol. 1985 Jul;101(1):257–268. doi: 10.1083/jcb.101.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kargacin G. J. Calcium signaling in restricted diffusion spaces. Biophys J. 1994 Jul;67(1):262–272. doi: 10.1016/S0006-3495(94)80477-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Keizer J., Smith G. D., Ponce-Dawson S., Pearson J. E. Saltatory propagation of Ca2+ waves by Ca2+ sparks. Biophys J. 1998 Aug;75(2):595–600. doi: 10.1016/S0006-3495(98)77550-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Keizer J., Smith G. D. Spark-to-wave transition: saltatory transmission of calcium waves in cardiac myocytes. Biophys Chem. 1998 May 5;72(1-2):87–100. doi: 10.1016/s0301-4622(98)00125-2. [DOI] [PubMed] [Google Scholar]
  33. Kupferman R., Mitra P. P., Hohenberg P. C., Wang S. S. Analytical calculation of intracellular calcium wave characteristics. Biophys J. 1997 Jun;72(6):2430–2444. doi: 10.1016/S0006-3495(97)78888-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lakatta E. G. Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart. Cardiovasc Res. 1992 Mar;26(3):193–214. doi: 10.1093/cvr/26.3.193. [DOI] [PubMed] [Google Scholar]
  35. Langer G. A., Peskoff A. Calcium concentration and movement in the diadic cleft space of the cardiac ventricular cell. Biophys J. 1996 Mar;70(3):1169–1182. doi: 10.1016/S0006-3495(96)79677-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lukyanenko V., Gyorke S. Ca2+ sparks and Ca2+ waves in saponin-permeabilized rat ventricular myocytes. J Physiol. 1999 Dec 15;521(Pt 3):575–585. doi: 10.1111/j.1469-7793.1999.00575.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lukyanenko V., Subramanian S., Gyorke I., Wiesner T. F., Gyorke S. The role of luminal Ca2+ in the generation of Ca2+ waves in rat ventricular myocytes. J Physiol. 1999 Jul 1;518(Pt 1):173–186. doi: 10.1111/j.1469-7793.1999.0173r.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ogata T., Yamasaki Y. Ultra-high resolution scanning electron microscopic studies on the sarcoplasmic reticulum and mitochondria in various muscles: a review. Scanning Microsc. 1993 Mar;7(1):145–156. [PubMed] [Google Scholar]
  39. Page E., McCallister L. P., Power B. Sterological measurements of cardiac ultrastructures implicated in excitation-contraction coupling. Proc Natl Acad Sci U S A. 1971 Jul;68(7):1465–1466. doi: 10.1073/pnas.68.7.1465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Parker I., Zang W. J., Wier W. G. Ca2+ sparks involving multiple Ca2+ release sites along Z-lines in rat heart cells. J Physiol. 1996 Nov 15;497(Pt 1):31–38. doi: 10.1113/jphysiol.1996.sp021747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Peskoff A., Langer G. A. Calcium concentration and movement in the ventricular cardiac cell during an excitation-contraction cycle. Biophys J. 1998 Jan;74(1):153–174. doi: 10.1016/S0006-3495(98)77776-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pratusevich V. R., Balke C. W. Factors shaping the confocal image of the calcium spark in cardiac muscle cells. Biophys J. 1996 Dec;71(6):2942–2957. doi: 10.1016/S0006-3495(96)79525-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shacklock P. S., Wier W. G., Balke C. W. Local Ca2+ transients (Ca2+ sparks) originate at transverse tubules in rat heart cells. J Physiol. 1995 Sep 15;487(Pt 3):601–608. doi: 10.1113/jphysiol.1995.sp020903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sipido K. R., Wier W. G. Flux of Ca2+ across the sarcoplasmic reticulum of guinea-pig cardiac cells during excitation-contraction coupling. J Physiol. 1991 Apr;435:605–630. doi: 10.1113/jphysiol.1991.sp018528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Smith G. D., Keizer J. E., Stern M. D., Lederer W. J., Cheng H. A simple numerical model of calcium spark formation and detection in cardiac myocytes. Biophys J. 1998 Jul;75(1):15–32. doi: 10.1016/S0006-3495(98)77491-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Stern M. D., Capogrossi M. C., Lakatta E. G. Spontaneous calcium release from the sarcoplasmic reticulum in myocardial cells: mechanisms and consequences. Cell Calcium. 1988 Dec;9(5-6):247–256. doi: 10.1016/0143-4160(88)90005-x. [DOI] [PubMed] [Google Scholar]
  47. Stern M. D. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992 Aug;63(2):497–517. doi: 10.1016/S0006-3495(92)81615-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Szalai G., Csordás G., Hantash B. M., Thomas A. P., Hajnóczky G. Calcium signal transmission between ryanodine receptors and mitochondria. J Biol Chem. 2000 May 19;275(20):15305–15313. doi: 10.1074/jbc.275.20.15305. [DOI] [PubMed] [Google Scholar]
  49. Takahashi A., Takamatsu T. Effects of basal [Ca2+]i on calcium handling in Ca(2+)-overloaded rat cultured heart muscle cells. Cell Signal. 1997 Dec;9(8):617–625. doi: 10.1016/s0898-6568(97)00068-5. [DOI] [PubMed] [Google Scholar]
  50. Takamatsu T., Wier W. G. Calcium waves in mammalian heart: quantification of origin, magnitude, waveform, and velocity. FASEB J. 1990 Mar;4(5):1519–1525. doi: 10.1096/fasebj.4.5.2307330. [DOI] [PubMed] [Google Scholar]
  51. Tang Y., Othmer H. G. A model of calcium dynamics in cardiac myocytes based on the kinetics of ryanodine-sensitive calcium channels. Biophys J. 1994 Dec;67(6):2223–2235. doi: 10.1016/S0006-3495(94)80707-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Trafford A. W., Lipp P., O'Neill S. C., Niggli E., Eisner D. A. Propagating calcium waves initiated by local caffeine application in rat ventricular myocytes. J Physiol. 1995 Dec 1;489(Pt 2):319–326. doi: 10.1113/jphysiol.1995.sp021053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wagner J., Keizer J. Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. Biophys J. 1994 Jul;67(1):447–456. doi: 10.1016/S0006-3495(94)80500-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Williams D. A., Delbridge L. M., Cody S. H., Harris P. J., Morgan T. O. Spontaneous and propagated calcium release in isolated cardiac myocytes viewed by confocal microscopy. Am J Physiol. 1992 Mar;262(3 Pt 1):C731–C742. doi: 10.1152/ajpcell.1992.262.3.C731. [DOI] [PubMed] [Google Scholar]
  55. Wussling M. H., Salz H. Nonlinear propagation of spherical calcium waves in rat cardiac myocytes. Biophys J. 1996 Mar;70(3):1144–1153. doi: 10.1016/S0006-3495(96)79715-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wussling M. H., Scheufler K., Schmerling S., Drygalla V. Velocity-curvature relationship of colliding spherical calcium waves in rat cardiac myocytes. Biophys J. 1997 Sep;73(3):1232–1242. doi: 10.1016/S0006-3495(97)78156-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Yao Y., Choi J., Parker I. Quantal puffs of intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes. J Physiol. 1995 Feb 1;482(Pt 3):533–553. doi: 10.1113/jphysiol.1995.sp020538. [DOI] [PMC free article] [PubMed] [Google Scholar]

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