Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Dec;79(6):2880–2892. doi: 10.1016/S0006-3495(00)76525-8

The phantom burster model for pancreatic beta-cells.

R Bertram 1, J Previte 1, A Sherman 1, T A Kinard 1, L S Satin 1
PMCID: PMC1301167  PMID: 11106596

Abstract

Pancreatic beta-cells exhibit bursting oscillations with a wide range of periods. Whereas periods in isolated cells are generally either a few seconds or a few minutes, in intact islets of Langerhans they are intermediate (10-60 s). We develop a mathematical model for beta-cell electrical activity capable of generating this wide range of bursting oscillations. Unlike previous models, bursting is driven by the interaction of two slow processes, one with a relatively small time constant (1-5 s) and the other with a much larger time constant (1-2 min). Bursting on the intermediate time scale is generated without need for a slow process having an intermediate time constant, hence phantom bursting. The model suggests that isolated cells exhibiting a fast pattern may nonetheless possess slower processes that can be brought out by injecting suitable exogenous currents. Guided by this, we devise an experimental protocol using the dynamic clamp technique that reliably elicits islet-like, medium period oscillations from isolated cells. Finally, we show that strong electrical coupling between a fast burster and a slow burster can produce synchronized medium bursting, suggesting that islets may be composed of cells that are intrinsically either fast or slow, with few or none that are intrinsically medium.

Full Text

The Full Text of this article is available as a PDF (209.5 KB).

Selected References

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

  1. Atwater I., Dawson C. M., Scott A., Eddlestone G., Rojas E. The nature of the oscillatory behaviour in electrical activity from pancreatic beta-cell. Horm Metab Res Suppl. 1980;Suppl 10:100–107. [PubMed] [Google Scholar]
  2. Atwater I., Rosario L., Rojas E. Properties of the Ca-activated K+ channel in pancreatic beta-cells. Cell Calcium. 1983 Dec;4(5-6):451–461. doi: 10.1016/0143-4160(83)90021-0. [DOI] [PubMed] [Google Scholar]
  3. Barbosa R. M., Silva A. M., Tomé A. R., Stamford J. A., Santos R. M., Rosário L. M. Control of pulsatile 5-HT/insulin secretion from single mouse pancreatic islets by intracellular calcium dynamics. J Physiol. 1998 Jul 1;510(Pt 1):135–143. doi: 10.1111/j.1469-7793.1998.135bz.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bergsten P. Slow and fast oscillations of cytoplasmic Ca2+ in pancreatic islets correspond to pulsatile insulin release. Am J Physiol. 1995 Feb;268(2 Pt 1):E282–E287. doi: 10.1152/ajpendo.1995.268.2.E282. [DOI] [PubMed] [Google Scholar]
  5. Bertram R., Smolen P., Sherman A., Mears D., Atwater I., Martin F., Soria B. A role for calcium release-activated current (CRAC) in cholinergic modulation of electrical activity in pancreatic beta-cells. Biophys J. 1995 Jun;68(6):2323–2332. doi: 10.1016/S0006-3495(95)80414-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chay T. R. Effects of extracellular calcium on electrical bursting and intracellular and luminal calcium oscillations in insulin secreting pancreatic beta-cells. Biophys J. 1997 Sep;73(3):1673–1688. doi: 10.1016/S0006-3495(97)78199-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chay T. R. Electrical bursting and luminal calcium oscillation in excitable cell models. Biol Cybern. 1996 Nov;75(5):419–431. doi: 10.1007/s004220050307. [DOI] [PubMed] [Google Scholar]
  8. Chay T. R., Kang H. S. Role of single-channel stochastic noise on bursting clusters of pancreatic beta-cells. Biophys J. 1988 Sep;54(3):427–435. doi: 10.1016/S0006-3495(88)82976-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chay T. R., Keizer J. Minimal model for membrane oscillations in the pancreatic beta-cell. Biophys J. 1983 May;42(2):181–190. doi: 10.1016/S0006-3495(83)84384-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cook D. L., Perara E. Islet electrical pacemaker response to alpha-adrenergic stimulation. Diabetes. 1982 Nov;31(11):985–990. doi: 10.2337/diacare.31.11.985. [DOI] [PubMed] [Google Scholar]
  11. Detimary P., Gilon P., Henquin J. C. Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets. Biochem J. 1998 Jul 15;333(Pt 2):269–274. doi: 10.1042/bj3330269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Falke L. C., Gillis K. D., Pressel D. M., Misler S. 'Perforated patch recording' allows long-term monitoring of metabolite-induced electrical activity and voltage-dependent Ca2+ currents in pancreatic islet B cells. FEBS Lett. 1989 Jul 17;251(1-2):167–172. doi: 10.1016/0014-5793(89)81448-6. [DOI] [PubMed] [Google Scholar]
  13. Gall D., Susa I. Effect of Na/Ca exchange on plateau fraction and [Ca]i in models for bursting in pancreatic beta-cells. Biophys J. 1999 Jul;77(1):45–53. doi: 10.1016/S0006-3495(99)76871-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilon P., Henquin J. C. Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. J Biol Chem. 1992 Oct 15;267(29):20713–20720. [PubMed] [Google Scholar]
  15. Gilon P., Jonas J. C., Henquin J. C. Culture duration and conditions affect the oscillations of cytoplasmic calcium concentration induced by glucose in mouse pancreatic islets. Diabetologia. 1994 Oct;37(10):1007–1014. doi: 10.1007/BF00400464. [DOI] [PubMed] [Google Scholar]
  16. Göpel S. O., Kanno T., Barg S., Eliasson L., Galvanovskis J., Renström E., Rorsman P. Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of action potentials in mouse pancreatic beta cells. J Gen Physiol. 1999 Dec;114(6):759–770. doi: 10.1085/jgp.114.6.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Göpel S., Kanno T., Barg S., Galvanovskis J., Rorsman P. Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets. J Physiol. 1999 Dec 15;521(Pt 3):717–728. doi: 10.1111/j.1469-7793.1999.00717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Hopkins W. F., Satin L. S., Cook D. L. Inactivation kinetics and pharmacology distinguish two calcium currents in mouse pancreatic B-cells. J Membr Biol. 1991 Feb;119(3):229–239. doi: 10.1007/BF01868728. [DOI] [PubMed] [Google Scholar]
  20. Jonkers F. C., Jonas J. C., Gilon P., Henquin J. C. Influence of cell number on the characteristics and synchrony of Ca2+ oscillations in clusters of mouse pancreatic islet cells. J Physiol. 1999 Nov 1;520(Pt 3):839–849. doi: 10.1111/j.1469-7793.1999.00839.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Keizer J., Magnus G. ATP-sensitive potassium channel and bursting in the pancreatic beta cell. A theoretical study. Biophys J. 1989 Aug;56(2):229–242. doi: 10.1016/S0006-3495(89)82669-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Keizer J., Smolen P. Bursting electrical activity in pancreatic beta cells caused by Ca(2+)- and voltage-inactivated Ca2+ channels. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3897–3901. doi: 10.1073/pnas.88.9.3897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kinard T. A., Satin L. S. Temperature modulates the Ca2+ current of HIT-T15 and mouse pancreatic beta-cells. Cell Calcium. 1996 Dec;20(6):475–482. doi: 10.1016/s0143-4160(96)90089-5. [DOI] [PubMed] [Google Scholar]
  24. Kinard T. A., de Vries G., Sherman A., Satin L. S. Modulation of the bursting properties of single mouse pancreatic beta-cells by artificial conductances. Biophys J. 1999 Mar;76(3):1423–1435. doi: 10.1016/S0006-3495(99)77303-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kozak J. A., Misler S., Logothetis D. E. Characterization of a Ca2+-activated K+ current in insulin-secreting murine betaTC-3 cells. J Physiol. 1998 Jun 1;509(Pt 2):355–370. doi: 10.1111/j.1469-7793.1998.355bn.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Larsson O., Kindmark H., Brandstrom R., Fredholm B., Berggren P. O. Oscillations in KATP channel activity promote oscillations in cytoplasmic free Ca2+ concentration in the pancreatic beta cell. Proc Natl Acad Sci U S A. 1996 May 14;93(10):5161–5165. doi: 10.1073/pnas.93.10.5161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Leech C. A., Holz G. G., 4th, Habener J. F. Voltage-independent calcium channels mediate slow oscillations of cytosolic calcium that are glucose dependent in pancreatic beta-cells. Endocrinology. 1994 Jul;135(1):365–372. doi: 10.1210/endo.135.1.8013370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liu Y. J., Grapengiesser E., Gylfe E., Hellman B. Glucose induces oscillations of cytoplasmic Ca2+, Sr2+ and Ba2+ in pancreatic beta-cells without participation of the thapsigargin-sensitive store. Cell Calcium. 1995 Aug;18(2):165–173. doi: 10.1016/0143-4160(95)90007-1. [DOI] [PubMed] [Google Scholar]
  29. Liu Y. J., Grapengiesser E., Gylfe E., Hellman B. Glucose-induced oscillations of Ba2+ in pancreatic beta-cells occur without involvement of intracellular mobilization. Arch Biochem Biophys. 1994 Dec;315(2):387–392. doi: 10.1006/abbi.1994.1515. [DOI] [PubMed] [Google Scholar]
  30. Liu Y. J., Tengholm A., Grapengiesser E., Hellman B., Gylfe E. Origin of slow and fast oscillations of Ca2+ in mouse pancreatic islets. J Physiol. 1998 Apr 15;508(Pt 2):471–481. doi: 10.1111/j.1469-7793.1998.471bq.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Longo E. A., Tornheim K., Deeney J. T., Varnum B. A., Tillotson D., Prentki M., Corkey B. E. Oscillations in cytosolic free Ca2+, oxygen consumption, and insulin secretion in glucose-stimulated rat pancreatic islets. J Biol Chem. 1991 May 15;266(14):9314–9319. [PubMed] [Google Scholar]
  32. Ma M., Koester J. The role of K+ currents in frequency-dependent spike broadening in Aplysia R20 neurons: a dynamic-clamp analysis. J Neurosci. 1996 Jul 1;16(13):4089–4101. doi: 10.1523/JNEUROSCI.16-13-04089.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Maechler P., Kennedy E. D., Sebö E., Valeva A., Pozzan T., Wollheim C. B. Secretagogues modulate the calcium concentration in the endoplasmic reticulum of insulin-secreting cells. Studies in aequorin-expressing intact and permeabilized ins-1 cells. J Biol Chem. 1999 Apr 30;274(18):12583–12592. doi: 10.1074/jbc.274.18.12583. [DOI] [PubMed] [Google Scholar]
  34. Magnus G., Keizer J. Model of beta-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables. Am J Physiol. 1998 Apr;274(4 Pt 1):C1158–C1173. doi: 10.1152/ajpcell.1998.274.4.C1158. [DOI] [PubMed] [Google Scholar]
  35. Martin F., Sanchez-Andres J. V., Soria B. Slow [Ca2+]i oscillations induced by ketoisocaproate in single mouse pancreatic islets. Diabetes. 1995 Mar;44(3):300–305. doi: 10.2337/diab.44.3.300. [DOI] [PubMed] [Google Scholar]
  36. Martin F., Soria B. Amino acid-induced [Ca2+]i oscillations in single mouse pancreatic islets of Langerhans. J Physiol. 1995 Jul 15;486(Pt 2):361–371. doi: 10.1113/jphysiol.1995.sp020818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mears D., Sheppard N. F., Jr, Atwater I., Rojas E., Bertram R., Sherman A. Evidence that calcium release-activated current mediates the biphasic electrical activity of mouse pancreatic beta-cells. J Membr Biol. 1997 Jan 1;155(1):47–59. doi: 10.1007/s002329900157. [DOI] [PubMed] [Google Scholar]
  38. Miura Y., Henquin J. C., Gilon P. Emptying of intracellular Ca2+ stores stimulates Ca2+ entry in mouse pancreatic beta-cells by both direct and indirect mechanisms. J Physiol. 1997 Sep 1;503(Pt 2):387–398. doi: 10.1111/j.1469-7793.1997.387bh.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nilsson T., Schultz V., Berggren P. O., Corkey B. E., Tornheim K. Temporal patterns of changes in ATP/ADP ratio, glucose 6-phosphate and cytoplasmic free Ca2+ in glucose-stimulated pancreatic beta-cells. Biochem J. 1996 Feb 15;314(Pt 1):91–94. doi: 10.1042/bj3140091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rae J., Cooper K., Gates P., Watsky M. Low access resistance perforated patch recordings using amphotericin B. J Neurosci Methods. 1991 Mar;37(1):15–26. doi: 10.1016/0165-0270(91)90017-t. [DOI] [PubMed] [Google Scholar]
  41. Roe M. W., Spencer B., Lancaster M. E., Mertz R. J., Worley J. F., 3rd, Dukes I. D. Absence of effect of culture duration on glucose-activated alterations in intracellular calcium concentration in mouse pancreatic islets. Diabetologia. 1995 Jul;38(7):876–879. doi: 10.1007/BF03035309. [DOI] [PubMed] [Google Scholar]
  42. Roe M. W., Worley J. F., 3rd, Qian F., Tamarina N., Mittal A. A., Dralyuk F., Blair N. T., Mertz R. J., Philipson L. H., Dukes I. D. Characterization of a Ca2+ release-activated nonselective cation current regulating membrane potential and [Ca2+]i oscillations in transgenically derived beta-cells. J Biol Chem. 1998 Apr 24;273(17):10402–10410. doi: 10.1074/jbc.273.17.10402. [DOI] [PubMed] [Google Scholar]
  43. Rorsman P., Trube G. Calcium and delayed potassium currents in mouse pancreatic beta-cells under voltage-clamp conditions. J Physiol. 1986 May;374:531–550. doi: 10.1113/jphysiol.1986.sp016096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rosário L. M., Barbosa R. M., Antunes C. M., Silva A. M., Abrunhosa A. J., Santos R. M. Bursting electrical activity in pancreatic beta-cells: evidence that the channel underlying the burst is sensitive to Ca2+ influx through L-type Ca2+ channels. Pflugers Arch. 1993 Sep;424(5-6):439–447. doi: 10.1007/BF00374906. [DOI] [PubMed] [Google Scholar]
  45. Satin L. S., Cook D. L. Evidence for two calcium currents in insulin-secreting cells. Pflugers Arch. 1988 Apr;411(4):401–409. doi: 10.1007/BF00587719. [DOI] [PubMed] [Google Scholar]
  46. Satin L. S., Tavalin S. J., Smolen P. D. Inactivation of HIT cell Ca2+ current by a simulated burst of Ca2+ action potentials. Biophys J. 1994 Jan;66(1):141–148. doi: 10.1016/S0006-3495(94)80759-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sharp A. A., O'Neil M. B., Abbott L. F., Marder E. Dynamic clamp: computer-generated conductances in real neurons. J Neurophysiol. 1993 Mar;69(3):992–995. doi: 10.1152/jn.1993.69.3.992. [DOI] [PubMed] [Google Scholar]
  48. Sherman A., Rinzel J., Keizer J. Emergence of organized bursting in clusters of pancreatic beta-cells by channel sharing. Biophys J. 1988 Sep;54(3):411–425. doi: 10.1016/S0006-3495(88)82975-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Smith P. A., Ashcroft F. M., Rorsman P. Simultaneous recordings of glucose dependent electrical activity and ATP-regulated K(+)-currents in isolated mouse pancreatic beta-cells. FEBS Lett. 1990 Feb 12;261(1):187–190. doi: 10.1016/0014-5793(90)80667-8. [DOI] [PubMed] [Google Scholar]
  50. Smolen P., Keizer J. Slow voltage inactivation of Ca2+ currents and bursting mechanisms for the mouse pancreatic beta-cell. J Membr Biol. 1992 Apr;127(1):9–19. doi: 10.1007/BF00232754. [DOI] [PubMed] [Google Scholar]
  51. Smolen P., Rinzel J., Sherman A. Why pancreatic islets burst but single beta cells do not. The heterogeneity hypothesis. Biophys J. 1993 Jun;64(6):1668–1680. doi: 10.1016/S0006-3495(93)81539-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sánchez-Andrés J. V., Gomis A., Valdeolmillos M. The electrical activity of mouse pancreatic beta-cells recorded in vivo shows glucose-dependent oscillations. J Physiol. 1995 Jul 1;486(Pt 1):223–228. doi: 10.1113/jphysiol.1995.sp020804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tengholm A., Hagman C., Gylfe E., Hellman B. In situ characterization of nonmitochondrial Ca2+ stores in individual pancreatic beta-cells. Diabetes. 1998 Aug;47(8):1224–1230. doi: 10.2337/diab.47.8.1224. [DOI] [PubMed] [Google Scholar]
  54. Turrigiano G. G., Marder E., Abbott L. F. Cellular short-term memory from a slow potassium conductance. J Neurophysiol. 1996 Feb;75(2):963–966. doi: 10.1152/jn.1996.75.2.963. [DOI] [PubMed] [Google Scholar]

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

RESOURCES