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. 1997 Feb;72(2 Pt 1):674–690. doi: 10.1016/s0006-3495(97)78704-6

Modeling Buffered Ca2+ Diffusion Near the Membrane

Implications for Secretion in Neuroendocrine Cells

Jürgen Klingauf 1, Erwin Neher 1
PMCID: PMC1185593  PMID: 9017195

Abstract

Secretion of catecholamines from neuroendocrine cells is relatively slow and it is likely that redistribution and buffering of Ca2+ is a major factor for delaying the response after a stimulus. In fact, in a recent study (Chow, R. H., J. Klingauf, and E. Neher. 1994. Time course of Ca2+ concentration triggering exocytosis in neuroendocrine cells. Proc. Natl. Acad. Sci. U.S.A. 91:12765-12769) Chow et al. concluded that the concentration of free calcium ([Ca2+]i) at a release site peaks at <10 μM during short-step depolarizations, and then decays to baseline over tens of milliseconds. To check whether such a time course is consistent with diffusion theory, we modeled buffered diffusion in the vicinity of a Ca2+ channel pore. Peak [Ca2+]i and the slow decay were well simulated when release-ready granules were randomly distributed within a regular grid of Ca2+ channels with mean interchannel distances of 300-600 nm. For such large spacings, however, the initial rise in [Ca2+]i was underestimated, suggesting that a small fraction of the release-ready pool (∼10%) experiences much higher [Ca2+]i, and thus might be collocalized with Ca2+ channels. A model that accommodates these findings then correctly predicts many recent observations, including the result that single action potentials evoke near-synchronous transmitter release with low quantal yield, whereas trains of action potentials lead to desynchronized release, but with severalfold increased quantal yield. The simulations emphasize the role of Ca2+ not only in triggering, but also in modulating the secretory response: buffers are locally depleted by residual Ca2+ of a preceding stimulus, so that a second pulse leads to a larger peak [Ca2+]i at the fusion sites.

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Selected References

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

  1. Adler E. M., Augustine G. J., Duffy S. N., Charlton M. P. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J Neurosci. 1991 Jun;11(6):1496–1507. doi: 10.1523/JNEUROSCI.11-06-01496.1991. [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. Artalejo C. R., Perlman R. L., Fox A. P. Omega-conotoxin GVIA blocks a Ca2+ current in bovine chromaffin cells that is not of the "classic" N type. Neuron. 1992 Jan;8(1):85–95. doi: 10.1016/0896-6273(92)90110-y. [DOI] [PubMed] [Google Scholar]
  4. Augustine G. J., Charlton M. P., Smith S. J. Calcium entry and transmitter release at voltage-clamped nerve terminals of squid. J Physiol. 1985 Oct;367:163–181. doi: 10.1113/jphysiol.1985.sp015819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bruns D., Jahn R. Real-time measurement of transmitter release from single synaptic vesicles. Nature. 1995 Sep 7;377(6544):62–65. doi: 10.1038/377062a0. [DOI] [PubMed] [Google Scholar]
  6. Chad J. E., Eckert R. Calcium domains associated with individual channels can account for anomalous voltage relations of CA-dependent responses. Biophys J. 1984 May;45(5):993–999. doi: 10.1016/S0006-3495(84)84244-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chow R. H., Klingauf J., Heinemann C., Zucker R. S., Neher E. Mechanisms determining the time course of secretion in neuroendocrine cells. Neuron. 1996 Feb;16(2):369–376. doi: 10.1016/s0896-6273(00)80054-9. [DOI] [PubMed] [Google Scholar]
  8. Chow R. H., Klingauf J., Neher E. Time course of Ca2+ concentration triggering exocytosis in neuroendocrine cells. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12765–12769. doi: 10.1073/pnas.91.26.12765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chow R. H., von Rüden L., Neher E. Delay in vesicle fusion revealed by electrochemical monitoring of single secretory events in adrenal chromaffin cells. Nature. 1992 Mar 5;356(6364):60–63. doi: 10.1038/356060a0. [DOI] [PubMed] [Google Scholar]
  10. Cox J. A., Milos M., MacManus J. P. Calcium- and magnesium-binding properties of oncomodulin. Direct binding studies and microcalorimetry. J Biol Chem. 1990 Apr 25;265(12):6633–6637. [PubMed] [Google Scholar]
  11. Engisch K. L., Nowycky M. C. Calcium dependence of large dense-cored vesicle exocytosis evoked by calcium influx in bovine adrenal chromaffin cells. J Neurosci. 1996 Feb 15;16(4):1359–1369. doi: 10.1523/JNEUROSCI.16-04-01359.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fenwick E. M., Marty A., Neher E. Sodium and calcium channels in bovine chromaffin cells. J Physiol. 1982 Oct;331:599–635. doi: 10.1113/jphysiol.1982.sp014394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fogelson A. L., Zucker R. S. Presynaptic calcium diffusion from various arrays of single channels. Implications for transmitter release and synaptic facilitation. Biophys J. 1985 Dec;48(6):1003–1017. doi: 10.1016/S0006-3495(85)83863-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Forsén S., Linse S., Thulin E., Lindegård B., Martin S. R., Bayley P. M., Brodin P., Grundström T. Kinetics of calcium binding to calbindin mutants. Eur J Biochem. 1988 Oct 15;177(1):47–52. doi: 10.1111/j.1432-1033.1988.tb14343.x. [DOI] [PubMed] [Google Scholar]
  15. Gamble E., Koch C. The dynamics of free calcium in dendritic spines in response to repetitive synaptic input. Science. 1987 Jun 5;236(4806):1311–1315. doi: 10.1126/science.3495885. [DOI] [PubMed] [Google Scholar]
  16. Geppert M., Goda Y., Hammer R. E., Li C., Rosahl T. W., Stevens C. F., Südhof T. C. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell. 1994 Nov 18;79(4):717–727. doi: 10.1016/0092-8674(94)90556-8. [DOI] [PubMed] [Google Scholar]
  17. Goda Y., Stevens C. F. Two components of transmitter release at a central synapse. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12942–12946. doi: 10.1073/pnas.91.26.12942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gold J. I., Bear M. F. A model of dendritic spine Ca2+ concentration exploring possible bases for a sliding synaptic modification threshold. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3941–3945. doi: 10.1073/pnas.91.9.3941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heidelberger R., Heinemann C., Neher E., Matthews G. Calcium dependence of the rate of exocytosis in a synaptic terminal. Nature. 1994 Oct 6;371(6497):513–515. doi: 10.1038/371513a0. [DOI] [PubMed] [Google Scholar]
  20. Heinemann C., Chow R. H., Neher E., Zucker R. S. Kinetics of the secretory response in bovine chromaffin cells following flash photolysis of caged Ca2+. Biophys J. 1994 Dec;67(6):2546–2557. doi: 10.1016/S0006-3495(94)80744-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Heizmann C. W., Braun K. Changes in Ca(2+)-binding proteins in human neurodegenerative disorders. Trends Neurosci. 1992 Jul;15(7):259–264. doi: 10.1016/0166-2236(92)90067-i. [DOI] [PubMed] [Google Scholar]
  22. Hines M. Efficient computation of branched nerve equations. Int J Biomed Comput. 1984 Jan-Feb;15(1):69–76. doi: 10.1016/0020-7101(84)90008-4. [DOI] [PubMed] [Google Scholar]
  23. Horrigan F. T., Bookman R. J. Releasable pools and the kinetics of exocytosis in adrenal chromaffin cells. Neuron. 1994 Nov;13(5):1119–1129. doi: 10.1016/0896-6273(94)90050-7. [DOI] [PubMed] [Google Scholar]
  24. Jackson A. P., Timmerman M. P., Bagshaw C. R., Ashley C. C. The kinetics of calcium binding to fura-2 and indo-1. FEBS Lett. 1987 May 25;216(1):35–39. doi: 10.1016/0014-5793(87)80752-4. [DOI] [PubMed] [Google Scholar]
  25. Kao J. P., Tsien R. Y. Ca2+ binding kinetics of fura-2 and azo-1 from temperature-jump relaxation measurements. Biophys J. 1988 Apr;53(4):635–639. doi: 10.1016/S0006-3495(88)83142-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Littleton J. T., Bellen H. J. Synaptotagmin controls and modulates synaptic-vesicle fusion in a Ca(2+)-dependent manner. Trends Neurosci. 1995 Apr;18(4):177–183. doi: 10.1016/0166-2236(95)93898-8. [DOI] [PubMed] [Google Scholar]
  28. Llinás R., Steinberg I. Z., Walton K. Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys J. 1981 Mar;33(3):323–351. doi: 10.1016/S0006-3495(81)84899-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Monck J. R., Robinson I. M., Escobar A. L., Vergara J. L., Fernandez J. M. Pulsed laser imaging of rapid Ca2+ gradients in excitable cells. Biophys J. 1994 Aug;67(2):505–514. doi: 10.1016/S0006-3495(94)80554-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Neher E., Marty A. Discrete changes of cell membrane capacitance observed under conditions of enhanced secretion in bovine adrenal chromaffin cells. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6712–6716. doi: 10.1073/pnas.79.21.6712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Neher E., Penner R. Mice sans synaptotagmin. Nature. 1994 Nov 24;372(6504):316–317. doi: 10.1038/372316a0. [DOI] [PubMed] [Google Scholar]
  33. Neher E., Zucker R. S. Multiple calcium-dependent processes related to secretion in bovine chromaffin cells. Neuron. 1993 Jan;10(1):21–30. doi: 10.1016/0896-6273(93)90238-m. [DOI] [PubMed] [Google Scholar]
  34. Nowycky M. C., Pinter M. J. Time courses of calcium and calcium-bound buffers following calcium influx in a model cell. Biophys J. 1993 Jan;64(1):77–91. doi: 10.1016/S0006-3495(93)81342-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. O'Sullivan A. J., Cheek T. R., Moreton R. B., Berridge M. J., Burgoyne R. D. Localization and heterogeneity of agonist-induced changes in cytosolic calcium concentration in single bovine adrenal chromaffin cells from video imaging of fura-2. EMBO J. 1989 Feb;8(2):401–411. doi: 10.1002/j.1460-2075.1989.tb03391.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Parnas H., Hovav G., Parnas I. Effect of Ca2+ diffusion on the time course of neurotransmitter release. Biophys J. 1989 May;55(5):859–874. doi: 10.1016/S0006-3495(89)82885-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Peng Y. Y., Zucker R. S. Release of LHRH is linearly related to the time integral of presynaptic Ca2+ elevation above a threshold level in bullfrog sympathetic ganglia. Neuron. 1993 Mar;10(3):465–473. doi: 10.1016/0896-6273(93)90334-n. [DOI] [PubMed] [Google Scholar]
  38. Prakriya M., Solaro C. R., Lingle C. J. [Ca2+]i elevations detected by BK channels during Ca2+ influx and muscarine-mediated release of Ca2+ from intracellular stores in rat chromaffin cells. J Neurosci. 1996 Jul 15;16(14):4344–4359. doi: 10.1523/JNEUROSCI.16-14-04344.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rahamimoff R., Yaari Y. Delayed release of transmitter at the frog neuromuscular junction. J Physiol. 1973 Jan;228(1):241–257. doi: 10.1113/jphysiol.1973.sp010084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roberts W. M. Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells. J Neurosci. 1994 May;14(5 Pt 2):3246–3262. doi: 10.1523/JNEUROSCI.14-05-03246.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sala F., Hernández-Cruz A. Calcium diffusion modeling in a spherical neuron. Relevance of buffering properties. Biophys J. 1990 Feb;57(2):313–324. doi: 10.1016/S0006-3495(90)82533-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schroeder T. J., Jankowski J. A., Senyshyn J., Holz R. W., Wightman R. M. Zones of exocytotic release on bovine adrenal medullary cells in culture. J Biol Chem. 1994 Jun 24;269(25):17215–17220. [PubMed] [Google Scholar]
  43. Seward E. P., Nowycky M. C. Kinetics of stimulus-coupled secretion in dialyzed bovine chromaffin cells in response to trains of depolarizing pulses. J Neurosci. 1996 Jan 15;16(2):553–562. doi: 10.1523/JNEUROSCI.16-02-00553.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Simon S. M., Llinás R. R. Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release. Biophys J. 1985 Sep;48(3):485–498. doi: 10.1016/S0006-3495(85)83804-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Stern M. D. Buffering of calcium in the vicinity of a channel pore. Cell Calcium. 1992 Mar;13(3):183–192. doi: 10.1016/0143-4160(92)90046-u. [DOI] [PubMed] [Google Scholar]
  46. Thomas-Reetz A. C., De Camilli P. A role for synaptic vesicles in non-neuronal cells: clues from pancreatic beta cells and from chromaffin cells. FASEB J. 1994 Feb;8(2):209–216. doi: 10.1096/fasebj.8.2.7907072. [DOI] [PubMed] [Google Scholar]
  47. Thomas P., Wong J. G., Lee A. K., Almers W. A low affinity Ca2+ receptor controls the final steps in peptide secretion from pituitary melanotrophs. Neuron. 1993 Jul;11(1):93–104. doi: 10.1016/0896-6273(93)90274-u. [DOI] [PubMed] [Google Scholar]
  48. Timmerman M. P., Ashley C. C. Fura-2 diffusion and its use as an indicator of transient free calcium changes in single striated muscle cells. FEBS Lett. 1986 Dec 1;209(1):1–8. doi: 10.1016/0014-5793(86)81073-0. [DOI] [PubMed] [Google Scholar]
  49. Verhage M., McMahon H. T., Ghijsen W. E., Boomsma F., Scholten G., Wiegant V. M., Nicholls D. G. Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals. Neuron. 1991 Apr;6(4):517–524. doi: 10.1016/0896-6273(91)90054-4. [DOI] [PubMed] [Google Scholar]
  50. Yamada W. M., Zucker R. S. Time course of transmitter release calculated from simulations of a calcium diffusion model. Biophys J. 1992 Mar;61(3):671–682. doi: 10.1016/S0006-3495(92)81872-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zhou Z., Misler S. Action potential-induced quantal secretion of catecholamines from rat adrenal chromaffin cells. J Biol Chem. 1995 Feb 24;270(8):3498–3505. [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]
  53. von Gersdorff H., Matthews G. Dynamics of synaptic vesicle fusion and membrane retrieval in synaptic terminals. Nature. 1994 Feb 24;367(6465):735–739. doi: 10.1038/367735a0. [DOI] [PubMed] [Google Scholar]
  54. von Rüden L., Neher E. A Ca-dependent early step in the release of catecholamines from adrenal chromaffin cells. Science. 1993 Nov 12;262(5136):1061–1065. doi: 10.1126/science.8235626. [DOI] [PubMed] [Google Scholar]

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