Skip to main content
Biophysical Journal logoLink to Biophysical Journal
. 2002 Dec;83(6):3134–3151. doi: 10.1016/S0006-3495(02)75317-4

Spatiotemporal features of Ca2+ buffering and diffusion in atrial cardiac myocytes with inhibited sarcoplasmic reticulum.

Anushka Michailova 1, Franco DelPrincipe 1, Marcel Egger 1, Ernst Niggli 1
PMCID: PMC1302392  PMID: 12496084

Abstract

Ca(2+) signaling in cells is largely governed by Ca(2+) diffusion and Ca(2+) binding to mobile and stationary Ca(2+) buffers, including organelles. To examine Ca(2+) signaling in cardiac atrial myocytes, a mathematical model of Ca(2+) diffusion was developed which represents several subcellular compartments, including a subsarcolemmal space with restricted diffusion, a myofilament space, and the cytosol. The model was used to quantitatively simulate experimental Ca(2+) signals in terms of amplitude, time course, and spatial features. For experimental reference data, L-type Ca(2+) currents were recorded from atrial cells with the whole-cell voltage-clamp technique. Ca(2+) signals were simultaneously imaged with the fluorescent Ca(2+) indicator Fluo-3 and a laser-scanning confocal microscope. The simulations indicate that in atrial myocytes lacking T-tubules, Ca(2+) movement from the cell membrane to the center of the cells relies strongly on the presence of mobile Ca(2+) buffers, particularly when the sarcoplasmic reticulum is inhibited pharmacologically. Furthermore, during the influx of Ca(2+) large and steep concentration gradients are predicted between the cytosol and the submicroscopically narrow subsarcolemmal space. In addition, the computations revealed that, despite its low Ca(2+) affinity, ATP acts as a significant buffer and carrier for Ca(2+), even at the modest elevations of [Ca(2+)](i) reached during influx of Ca(2+).

Full Text

The Full Text of this article is available as a PDF (578.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adachi-Akahane S., Cleemann L., Morad M. Cross-signaling between L-type Ca2+ channels and ryanodine receptors in rat ventricular myocytes. J Gen Physiol. 1996 Nov;108(5):435–454. doi: 10.1085/jgp.108.5.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Backx P. H., de Tombe P. P., Van Deen J. H., Mulder B. J., ter Keurs H. E. A model of propagating calcium-induced calcium release mediated by calcium diffusion. J Gen Physiol. 1989 May;93(5):963–977. doi: 10.1085/jgp.93.5.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baylor S. M., Hollingworth S. Model of sarcomeric Ca2+ movements, including ATP Ca2+ binding and diffusion, during activation of frog skeletal muscle. J Gen Physiol. 1998 Sep;112(3):297–316. doi: 10.1085/jgp.112.3.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berlin J. R., Bassani J. W., Bers D. M. Intrinsic cytosolic calcium buffering properties of single rat cardiac myocytes. Biophys J. 1994 Oct;67(4):1775–1787. doi: 10.1016/S0006-3495(94)80652-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burt J. M., Langer G. A. Ca2+ displacement by Polymyxin B from sarcolemma isolated by 'gas dissection' from cultured neonatal rat myocardial cells. Biochim Biophys Acta. 1983 Mar 23;729(1):44–52. doi: 10.1016/0005-2736(83)90454-6. [DOI] [PubMed] [Google Scholar]
  7. Cannell M. B., Allen D. G. Model of calcium movements during activation in the sarcomere of frog skeletal muscle. Biophys J. 1984 May;45(5):913–925. doi: 10.1016/S0006-3495(84)84238-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cannell M. B., Berlin J. R., Lederer W. J. Effect of membrane potential changes on the calcium transient in single rat cardiac muscle cells. Science. 1987 Dec 4;238(4832):1419–1423. doi: 10.1126/science.2446391. [DOI] [PubMed] [Google Scholar]
  9. Carafoli E. The homeostasis of calcium in heart cells. J Mol Cell Cardiol. 1985 Mar;17(3):203–212. doi: 10.1016/s0022-2828(85)80003-1. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Cheng H., Lederer W. J., Cannell M. B. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993 Oct 29;262(5134):740–744. doi: 10.1126/science.8235594. [DOI] [PubMed] [Google Scholar]
  12. Cordeiro J. M., Spitzer K. W., Giles W. R., Ershler P. E., Cannell M. B., Bridge J. H. Location of the initiation site of calcium transients and sparks in rabbit heart Purkinje cells. J Physiol. 2001 Mar 1;531(Pt 2):301–314. doi: 10.1111/j.1469-7793.2001.0301i.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Eberhard M., Erne P. Kinetics of calcium binding to fluo-3 determined by stopped-flow fluorescence. Biochem Biophys Res Commun. 1989 Aug 30;163(1):309–314. doi: 10.1016/0006-291x(89)92136-0. [DOI] [PubMed] [Google Scholar]
  15. Egger M., Niggli E. Regulatory function of Na-Ca exchange in the heart: milestones and outlook. J Membr Biol. 1999 Mar 15;168(2):107–130. doi: 10.1007/s002329900502. [DOI] [PubMed] [Google Scholar]
  16. Ellis-Davies G. C., Kaplan J. H., Barsotti R. J. Laser photolysis of caged calcium: rates of calcium release by nitrophenyl-EGTA and DM-nitrophen. Biophys J. 1996 Feb;70(2):1006–1016. doi: 10.1016/S0006-3495(96)79644-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Fawcett D. W., McNutt N. S. The ultrastructure of the cat myocardium. I. Ventricular papillary muscle. J Cell Biol. 1969 Jul;42(1):1–45. doi: 10.1083/jcb.42.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Gabso M., Neher E., Spira M. E. Low mobility of the Ca2+ buffers in axons of cultured Aplysia neurons. Neuron. 1997 Mar;18(3):473–481. doi: 10.1016/s0896-6273(00)81247-7. [DOI] [PubMed] [Google Scholar]
  21. Gómez A. M., Valdivia H. H., Cheng H., Lederer M. R., Santana L. F., Cannell M. B., McCune S. A., Altschuld R. A., Lederer W. J. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science. 1997 May 2;276(5313):800–806. doi: 10.1126/science.276.5313.800. [DOI] [PubMed] [Google Scholar]
  22. Haddock P. S., Coetzee W. A., Cho E., Porter L., Katoh H., Bers D. M., Jafri M. S., Artman M. Subcellular [Ca2+]i gradients during excitation-contraction coupling in newborn rabbit ventricular myocytes. Circ Res. 1999 Sep 3;85(5):415–427. doi: 10.1161/01.res.85.5.415. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Hüser J., Lipsius S. L., Blatter L. A. Calcium gradients during excitation-contraction coupling in cat atrial myocytes. J Physiol. 1996 Aug 1;494(Pt 3):641–651. doi: 10.1113/jphysiol.1996.sp021521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jafri M. S., Keizer J. On the roles of Ca2+ diffusion, Ca2+ buffers, and the endoplasmic reticulum in IP3-induced Ca2+ waves. Biophys J. 1995 Nov;69(5):2139–2153. doi: 10.1016/S0006-3495(95)80088-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jiang Y. H., Klein M. G., Schneider M. F. Numerical simulation of Ca2+ "sparks" in skeletal muscle. Biophys J. 1999 Nov;77(5):2333–2357. doi: 10.1016/s0006-3495(99)77072-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kargacin G., Fay F. S. Ca2+ movement in smooth muscle cells studied with one- and two-dimensional diffusion models. Biophys J. 1991 Nov;60(5):1088–1100. doi: 10.1016/S0006-3495(91)82145-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kargacin M. E., Kargacin G. J. Predicted changes in concentrations of free and bound ATP and ADP during intracellular Ca2+ signaling. Am J Physiol. 1997 Oct;273(4 Pt 1):C1416–C1426. doi: 10.1152/ajpcell.1997.273.4.C1416. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Klingauf J., Neher E. Modeling buffered Ca2+ diffusion near the membrane: implications for secretion in neuroendocrine cells. Biophys J. 1997 Feb;72(2 Pt 1):674–690. doi: 10.1016/s0006-3495(97)78704-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kockskämper J., Glitsch H. G. Sodium pump of cultured guinea pig atrial myocytes. Ann N Y Acad Sci. 1997 Nov 3;834:354–356. doi: 10.1111/j.1749-6632.1997.tb52269.x. [DOI] [PubMed] [Google Scholar]
  32. Kockskämper J., Sheehan K. A., Bare D. J., Lipsius S. L., Mignery G. A., Blatter L. A. Activation and propagation of Ca(2+) release during excitation-contraction coupling in atrial myocytes. Biophys J. 2001 Nov;81(5):2590–2605. doi: 10.1016/S0006-3495(01)75903-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kushmerick M. J., Podolsky R. J. Ionic mobility in muscle cells. Science. 1969 Dec 5;166(3910):1297–1298. doi: 10.1126/science.166.3910.1297. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Langer G. A., Rich T. L. Augmentation of sarcolemmal Ca by anionic amphiphile: contractile response of three ventricular tissues. Am J Physiol. 1986 Feb;250(2 Pt 2):H247–H254. doi: 10.1152/ajpheart.1986.250.2.H247. [DOI] [PubMed] [Google Scholar]
  36. Leblanc N., Hume J. R. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science. 1990 Apr 20;248(4953):372–376. doi: 10.1126/science.2158146. [DOI] [PubMed] [Google Scholar]
  37. Lederer W. J., Niggli E., Hadley R. W. Sodium-calcium exchange in excitable cells: fuzzy space. Science. 1990 Apr 20;248(4953):283–283. doi: 10.1126/science.2326638. [DOI] [PubMed] [Google Scholar]
  38. Lipp P., Lüscher C., Niggli E. Photolysis of caged compounds characterized by ratiometric confocal microscopy: a new approach to homogeneously control and measure the calcium concentration in cardiac myocytes. Cell Calcium. 1996 Mar;19(3):255–266. doi: 10.1016/s0143-4160(96)90026-3. [DOI] [PubMed] [Google Scholar]
  39. Lipp P., Pott L., Callewaert G., Carmeliet E. Simultaneous recording of Indo-1 fluorescence and Na+/Ca2+ exchange current reveals two components of Ca2(+)-release from sarcoplasmic reticulum of cardiac atrial myocytes. FEBS Lett. 1990 Nov 26;275(1-2):181–184. doi: 10.1016/0014-5793(90)81467-3. [DOI] [PubMed] [Google Scholar]
  40. Mackenzie L., Bootman M. D., Berridge M. J., Lipp P. Predetermined recruitment of calcium release sites underlies excitation-contraction coupling in rat atrial myocytes. J Physiol. 2001 Feb 1;530(Pt 3):417–429. doi: 10.1111/j.1469-7793.2001.0417k.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Neher E., Augustine G. J. Calcium gradients and buffers in bovine chromaffin cells. J Physiol. 1992 May;450:273–301. doi: 10.1113/jphysiol.1992.sp019127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Niggli E. Localized intracellular calcium signaling in muscle: calcium sparks and calcium quarks. Annu Rev Physiol. 1999;61:311–335. doi: 10.1146/annurev.physiol.61.1.311. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Post J. A., Langer G. A. Sarcolemmal calcium binding sites in heart: I. Molecular origin in "gas-dissected" sarcolemma. J Membr Biol. 1992 Jul;129(1):49–57. doi: 10.1007/BF00232054. [DOI] [PubMed] [Google Scholar]
  45. Robertson S. P., Johnson J. D., Potter J. D. The time-course of Ca2+ exchange with calmodulin, troponin, parvalbumin, and myosin in response to transient increases in Ca2+. Biophys J. 1981 Jun;34(3):559–569. doi: 10.1016/S0006-3495(81)84868-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ríos E., Ma J. J., González A. The mechanical hypothesis of excitation-contraction (EC) coupling in skeletal muscle. J Muscle Res Cell Motil. 1991 Apr;12(2):127–135. doi: 10.1007/BF01774031. [DOI] [PubMed] [Google Scholar]
  47. Schneider M. F., Chandler W. K. Voltage dependent charge movement of skeletal muscle: a possible step in excitation-contraction coupling. Nature. 1973 Mar 23;242(5395):244–246. doi: 10.1038/242244a0. [DOI] [PubMed] [Google Scholar]
  48. Soeller C., Cannell M. B. Numerical simulation of local calcium movements during L-type calcium channel gating in the cardiac diad. Biophys J. 1997 Jul;73(1):97–111. doi: 10.1016/S0006-3495(97)78051-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tang Y., Schlumpberger T., Kim T., Lueker M., Zucker R. S. Effects of mobile buffers on facilitation: experimental and computational studies. Biophys J. 2000 Jun;78(6):2735–2751. doi: 10.1016/s0006-3495(00)76819-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Taylor S. R., Rüdel R., Blinks J. R. Calcium transients in amphibian muscle. Fed Proc. 1975 Apr;34(5):1379–1381. [PubMed] [Google Scholar]
  51. 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]
  52. Zhou Z., Neher E. Mobile and immobile calcium buffers in bovine adrenal chromaffin cells. J Physiol. 1993 Sep;469:245–273. doi: 10.1113/jphysiol.1993.sp019813. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES