CoChat
Sign Up
Cited by 65Ion channel regulation and functionPancreatic function and diabetesIon Channels and Receptors

Calcium-activated K+ Channels of Mouse β-cells are Controlled by Both Store and Cytoplasmic Ca2+

Open access
Goforth, P.B., Bertram, R., Khan, F.A., Zhang, M., Sherman, A., Satin, L.S.·2002·The Journal of General Physiology
DOI 10.1085/jgp.20028581PMC PMC2229522
Open this paper in CoChat — free account

Abstract

A novel calcium-dependent potassium current (Kslow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic β-cells (Göpel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renström, and P. Rorsman. 1999. J. Gen. Physiol. 114:759–769). Kslow activation may help terminate the cyclic bursts of Ca2+-dependent action potentials that drive Ca2+ influx and insulin secretion in β-cells. Here, we report that when [Ca2+]i handling was disrupted by blocking Ca2+ uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1–5 μM) or insulin (200 nM), Kslow was transiently potentiated and then inhibited. Kslow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of Kslow by SERCA blockers could not be explained by a minimal mathematical model in which [Ca2+]i is divided between two compartments, the cytosol and the ER, and Kslow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which Kslow activation is mediated by a localized pool of [Ca2+] in a subspace located between the ER and the plasma membrane. In this model, the subspace [Ca2+] follows changes in cytosolic [Ca2+] but with a gradient that reflects Ca2+ efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of Kslow and [Ca2+] handling in influencing β-cell electrical activity and insulin secretion.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1085/jgp.20028581

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The reduction of Kslow in dispersed β-cells may account for the loss of normal oscillatory electrical activity seen in this preparation.

    “which may account for the loss of normal oscillatory electrical activity seen in this preparation (but see (217)).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [217]

    The Discussion describes the proposal that dispersed β-cells have less Kslow and that this explains their altered electrical activity, but rejects that explanation. It concludes that differences in Kslow amplitude are not sufficient to explain the electrical differences between dispersed and in situ β-cells. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • The modulation of Kslow by glucose may underlie the shortening of the electrically silent inter-burst intervals that occurs with increasing glucose concentrations.

    “The modulation of Kslow by glucose is of functional importance as it may underlie the shortening of the electrically silent inter-burst intervals that occurs with increasing glucose concentrations.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [217]

    The Results ('Modulation of Kslow by Glucose'; page unavailable) show that raising glucose from 5 to 10 mM reduces Kslow current density. The Introduction says increasing glucose shortens the silent phase, and the Results ('The Role of Kslow in Islet Bursting'; page unavailable) propose a role for Kslow in electrical oscillations. The paper does not specifically propose or test whether glucose's effect on Kslow accounts for that shortening. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The SERCA inhibitor thapsigargin exerts a dual effect on Kslow, transiently increasing and then reducing its amplitude.

    “It is interesting that the SERCA inhibitor thapsigargin exerts a dual effect on Kslow, transiently increasing and then reducing its amplitude (217).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [217]

  • The Kslow current is reduced by 50% when glucose is increased from 5 to 10 mM.

    “The Kslow current is reduced by 50% when glucose is increased from 5 to 10 mM (217).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [217]

  • [Ca2+]i buffering plays an important role in Kslow regulation.

    “This suggests [Ca2+]i buffering plays an important role in Kslow regulation.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [217]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 61

  1. Ämmala, C., O. Larsson, P.O. Berggren, K. Bokvist, L. Juntti-Berggren, H. Kindmark, and P. Rorsman. 1991. Inositol trisphosphate-dependent periodic activation of a Ca(2+)-activated K+ conductance in glucose-stimulated pancreatic beta-cells. Nature. 353: 849–852. 1719424
  2. Arredouani, A., J.C. Henquin, and P. Gilon. 2002 Contribution of the endoplasmic reticulum to the glucose-induced [Ca2+]c response in mouse pancreatic islets. Am. J. Physiol. Endocrinol. Metab. 282: 982–991. 11934662
  3. Ashcroft, F.M., and P. Rorsman. 1989. Electrophysiology of the pancreatic β-cell. Prog. Biophys. Mol. Biol. 54: 87–143. 2484976
  4. Atwater, I., C.M. Dawson, B. Ribalet, and E. Rojas. 1979. Potassium permeability activated by intracellular calcium ion concentration in the pancreatic β-cell. J. Physiol. 288: 575–588. 381636 PMC1281445
  5. Aulbach, F., A. Simm, S. Maier, H. Langenfeld, U. Walter, U. Kersting, and M. Kirstein. 1999. Insulin stimulates the L-type Ca2+ current in rat cardiac myocytes. Cardiovasc. Res. 44: 390–397. 10435002
  6. Barker, C.J., T. Nilsson, C.J. Kirk, R.H. Michell, and P.O. Berggren. 1994. Simultaneous oscillations of cytoplasmic free Ca2+ concentration and Ins(1,4,5)P3 concentration in mouse pancreatic beta-cells. Biochem. J. 297: 265–268. 8297329 PMC1137823
  7. Berridge, M.J. 1998. Neuronal calcium signaling. Neuron. 21: 13–26. 9697848
  8. Bers, D.M., and E. Perez-Reyes. 1999. Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release. Cardiovasc. Res. 42: 339–360. 10533572
  9. Bertram, R., P. Smolen, A. Sherman, D. Mears, I. Atwater, F. Martin, and B. Soria. 1995 A role for calcium-release activated current (CRAC) in cholinergic modulation of electrical activity in pancreatic β-cells. Biophys. J. 68: 23223–23232. PMC1282142 7647236
  10. Bertram, R., J. Previte, A. Sherman, T.A. Kinard, and L.S. Satin. 2000. The phantom burster model for pancreatic β-cells. Biophys. J. 79: 2880–2892. 11106596 PMC1301167
  11. Bootman, M.D., P. Lipp, and M.J. Berridge. 2001. The organisation and functions of local Ca2+ signals. J. Cell Sci. 114: 2213–2222. 11493661
  12. Carl, S.L., K. Felix, A.H. Caswell, N.R. Brandt, W.J. Ball, Jr., P.L. Vahgy, G. Meissner, and D.G. Ferguson. 1995. Immunolocalization of sarcolemmal dihydropyridine receptor and sarcoplasmic reticular triadin and ryanodine receptor in rabbit ventricle and atrium. J. Cell Biol. 129: 672–682. 7730403 PMC2120452
  13. Chay, T.R. 1996. Electrical bursting and luminal calcium oscillation in excitable cell models. Biol. Cybern. 75: 419–431. 8983163
  14. Chay, T.R. 1997. Effects of extracellular calcium on electrical bursting and intracellular and luminal calcium oscillations in insulin secreting pancreatic β-cells. Biophys. J. 73: 1673–1688. 9284334 PMC1181066
  15. Cook, D.L. 1984. Electrical pacemaker mechanisms of pancreatic islet cells. Fed. Proc. 43: 2368–2372. 6327396
  16. Cook, D.L., M. Ikeuchi, and W. Fujimoto. 1984 Voltage-dependence of rhythmic plateau potentials of pancreatic islet cells. Am. J. Physiol. 240: E290–E296. 7011053
  17. Cook, D.L., L.S. Satin, and W.F. Hopkins. 1991. Pancreatic β cells are bursting, but how? Trends Neurosci. 14: 411–414. 1720583
  18. Cordoba-Rodriguez, R., K.A. Moore, J.P. Kao, and D. Weinreich. 1999. Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons. Proc. Natl. Acad. Sci. USA. 96: 7650–7657. 10393875 PMC33596
  19. Dean, P.M., and E.K. Matthews. 1968. Electrical activity in pancreatic islet cells. Nature. 219: 389–390. 4873864
  20. Dean, P.M., and E.K. Matthews. 1970. Electrical activity of pancreatic islet cells: effect of ions. J. Physiol. 210: 265–275. 5501260 PMC1395563
  21. Falke, L.C., K.D. Gillis, D.M. Pressel, and S. Misler. 1989. ‘Perforated patch recording’ allows long-term monitoring of metabolite-induced electrical activity and voltage-dependent Ca2+ currents in pancreatic islet β cells. FEBS Lett. 251: 167–172. 2473925
  22. Frieden, M., and W.F. Graier. 2000. Subplasmalemmal ryanodine-sensitive Ca2+ release contributes to Ca2+-dependent K+ channel activation in human umbilical vein endothelial cell line. J. Physiol. 524: 715–724. 10790153 PMC2269913
  23. Gilon, P., A. Arredouani, P. Gailly, J. Gromada, and J.C. Henquin. 1999. Uptake and release of Ca2+ by the endoplasmic reticulum contribute to the oscillations of the cytosolic Ca2+ concentration triggered by Ca2+ influx in the electrically excitable pancreatic β-cell. J. Biol. Chem. 274: 20197–20205. 10400636
  24. Gilon, P., and J.C. Henquin. 1992. Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic β-cell. J. Biol. Chem. 267: 20713–20720. 1400388
  25. Gromada, J., J. Frokjaer-Jensen, and S. Dissing. 1996. Glucose stimulates voltage- and calcium-dependent inositol trisphosphate production and intracellular calcium mobilization in insulin-secreting beta TC3 cells. Biochem. J. 314: 339–345. 8660305 PMC1217047
  26. Hellman, B., E. Gylfe, E. Grapengiesser, P.E. Lund, and A. Berts. 1992 Cytoplasmic Ca2+ oscillations in pancreatic β-cells. Biochem. et Biophys Acta. 1113: 295–305. 1450203
  27. Hennige, A.M., N. Lembert, M.A. Wahl, and H.P. Ammo. 2000. Oxidative stress increases potassium efflux from pancreatic islets by depletion of intracellular calcium stores. Free Radic. Res. 33: 507–516. 11200084
  28. Herrington, J., and R.J. Bookman. 1994. Pulse Control v4.3 Igor XOPs for Patch Clamp Data Acquisition. University of Miami Press, Miami, FL.
  29. Hirschberg, B., J. Maylie, J.P. Adelman, and N.V. Marrion. 1998. Gating of recombinant small conductance Ca-activated K+ channels by calcium. J. Gen. Physiol. 111: 565–581. 9524139 PMC2217120
  30. Islam, M.S., I. Leibiger, B. Leibiger, D. Rossi, V. Sorrentino, T.J. Ekstrom, H. Westerblad, F.H. Andrade, and P.O. Berggren. 1998. In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation. Proc. Natl. Acad. Sci. USA. 95: 6145–6150. 9600932 PMC27605
  31. Islam, M.S., P. Rorsman, and P.O. Berggren. 1992. Ca2+-induced Ca2+ release in insulin-secreting cells. FEBS Lett. 296: 287–291. 1537406
  32. Jafri, M.S., J.J. Rice, and R.L. Winslow. 1998. Cardiac Ca2+ dynamics: the roles of ryanodine receptor adaptation and sarcoplasmic reticulum load. Biophys. J. 74: 1149–1168. 9512016 PMC1299466
  33. Khan, F.A., P.B. Goforth, M. Zhang, and L.S. Satin. 2001. Insulin activates ATP-sensitive K+ channels in pancreatic β-cells through a phosphatidylinositol 3-kinase-dependent pathway. Diabetes. 50: 2192–2198. 11574397
  34. Kinard, T.A., G. de Vries, A. Sherman, and L.S. Satin. 1999. Modulation of the bursting properties of single mouse pancreatic beta cells by artificial conductances. Biophys. J. 76: 1423–1435. 10049324 PMC1300120
  35. Kozak, J.A., S. Misler, and D.E. Logothetis. 1998. Characterization of a Ca2+-activated K+ current in insulin-secreting murine beta TC-3 cells. J. Physiol. 509: 355–370. 9575286 PMC2230977
  36. Kukuljan, M., A.A. Goncalves, and I. Atwater. 1991. Charybdotoxin-sensitive Kca channel is not involved in glucose-induced electrical activity in pancreatic β-cells. J. Membr. Biol. 119: 187–195. 1710672
  37. Larsson, O., H. Kindmark, R. Branstrom, B. Fredholm, and P.O. Berggren. 1996. Oscillations in KATP channel activity promote oscillations in cytoplasmic free Ca2+ concentration in the pancreatic β-cell. Proc. Natl. Acad. Sci. USA. 93: 5161–5165. 8643546 PMC39425
  38. Liu, Y.J., E. Grapengiesser, E. Gylfe, and B. Hellman. 1995. Glucose induces oscillations of cytoplasmic Ca2+, Sr2+, and Ba2+, in pancreatic β-cells without participation of the thapsigargin-sensitive store. Cell Calcium. 18: 165–173. 7585893
  39. Liu, Y.J., E. Grapengiesser, E. Gylfe, and B. Hellman. 1996. Crosstalk between the cAMP and inositol trisphosphate-signaling pathways in pancreatic beta-cells. Arch. Biochem. Biophys. 334: 295–302. 8900404
  40. Liu, Y.J., and E. Gylfe. 1997. Store-operated Ca2+ entry in insulin-releasing pancreatic beta-cells. Cell Calcium. 22: 277–286. 9481478
  41. Liu, X., E. Rojas, and I.S. Ambukar. 1998. Regulation of KCa current by store-operated Ca2+ influx depends on internal Ca2+ release in HSG cells. Am. J. Physiol. 275: C571–C580. 9688612
  42. Martín, F., J. Ribas, and B. Soria. 1997. Cytosolic Ca2+ gradients in pancreatic islet cells stimulated by glucose and carbachol. Biochem. Biophys. Res. Commun. 235: 465–468. 9207177
  43. Meissner, H.P., and H. Schmelz. 1974. Membrane potential of beta-cells in pancreatic islets. Pflugers Arch. 351: 195–206. 4608967
  44. Meissner, H.P., and W. Schmeer. 1981. The significance of calcium ions for the glucose-induced electrical activity of pancreatic β-cells. In The Mechanism of Gated Calcium Transport Across Biological Membranes. S. Ohnishi and M. Endo, editors. Academic Press, New York, NY. 324 pp.
  45. Miura, Y., J.C. Henquin, and P. Gilon. 1997. Emptying of intracellular Ca2+ stores stimulates Ca2+ entry in mouse pancreatic β-cells by both direct and indirect mechanisms. J. Physiol. 503: 387–398. 9306280 PMC1159870
  46. Petersen, O.H., A. Tepikin, and M.K. Park. 2001. The endoplasmic reticulum: one continuous or several separate Ca2+ stores? Trends Neurosci. 24(5): 271–276. 11311379
  47. Quesada, I., F. Martín, and B. Soria. 2000. Nutrient modulation of polarized and sustained submembrane Ca2+ microgradients in mouse pancreatic islet cells. J. Physiol. 525: 159–167. 10811734 PMC2269922
  48. Ribalet, B., and P.M. Beigelman. 1981. Effects of divalent cations on β-cell electrical activity. Am. J. Physiol. 241: C59–C67. 7018263
  49. Roe, M.W., J.F. Worley III, F. Qian, N. Tamarina, A.A. Mittal, F. Dralyuk, N.T. Blair, R.J. Mertz, L.H. Philipson, and I.D. Dukes. 1998. Characterization of a Ca2+ release-activated nonselective cation current regulating membrane potential and [Ca2+]I oscillations in transgenically derived beta-cells. J. Biol. Chem. 273: 10402–10410. 9553098
  50. Rorsman, P., and G. Trube. 1985. Glucose dependent K+ channels in pancreatic beta-cells are regulated by intracellular ATP. Pflugers Arch. 405: 305–309. 2417189
  51. Rosario, L.M., R.M. Barbosa, C.M. Antunes, A.M. Silva, A.J. Abrunhosa, and R.M. Santos. 1993. 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. 424: 439–447. 7504808
  52. Satin, L.S., and T.A. Kinard. 1998. Neurotransmitters and their receptors in the islets of Langerhans of the pancreas: what messages do acetylcholine, glutamate, and GABA transmit? Endocrine. 8: 213–223. 9741825
  53. Sherman, A. 1996 Contributions of modeling to understanding stimulus-secretion coupling in pancreatic β-cells. Am. J. Physiol. 34: E362–E372. 8770032
  54. Tengholm, A., C. Hagman, E. Gylfe, and B. Hellman. 1998. In situ characterization of nonmitochondrial Ca2+ stores in individual pancreatic β-cells. Diabetes. 47: 1224–1230. 9703321
  55. Tengholm, A., B. Hellman, and E. Gylfe. 2000. Mobilization of Ca2+ stores in individual pancreatic beta-cells permeabilized or not with digitonin or alpha-toxin. Cell Calcium. 27: 43–51. 10726210
  56. Tengholm, A., B. Hellman, and E. Gylfe. 2001. The endoplasmic reticulum is a glucose-modulated high-affinity sink for Ca2+ in mouse pancreatic beta-cells. J. Physiol. 530: 533–540. 11158282 PMC2278424
  57. Thastrup, O., P.J. Cullen, B.K. Drobak, M.R. Hanley, and A.P. Dawson. 1990. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc. Natl. Acad. Sci. USA. 87: 2466–2470. 2138778 PMC53710
  58. Wollheim, C.B., and W.G. Sharp. 1981. Regulation of insulin release by calcium. Physiol. Revs. 61: 914–973. 6117094
  59. Worley, J.F. III, M.S. McIntyre, B. Spencer, R.J. Mertz, M.W. Roe, and I.D. Dukes. 1994a. Endoplasmic reticulum calcium store depletion regulates membrane potential in mouse islet β-cells. J. Biol. Chem. 269: 14359–14362. 8182038
  60. Worley, J.F. III, M.S. McIntyre, B. Spencer, and I.D. Dukes. 1994b. Depletion of intracellular Ca2+ stores activates a maitotoxin-sensitive nonselective cationic current in beta-cells. J. Biol. Chem. 269: 32055–32058. 7798198
  61. Xu, G.G., Z.-Y. Gao, P.D. Borge, and B.A. Wolf. 1999. Insulin receptor substrate-1 induced inhibition of endoplasmic reticulum Ca2+ uptake in β-cells. J. Biol. Chem. 274: 18067–18074. 10364259

Cited by

Sorted by citations

Authors
Goforth, P. B., Bertram, R., Khan, F. A., Zhang, M., Sherman, A., & Satin, L. S.
Affiliations
  • Virginia Commonwealth University (US)
  • Florida State University (US)
  • National Institutes of Health (US)
ORCID
Venue
The Journal of General Physiology
Publisher
Rockefeller University Press
Published
2002-08-12
Volume
120
Issue
3
Pages
307-322
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
DOI
10.1085/jgp.20028581
PMC
PMC2229522
OpenAlex
W2131042436
Cited by
65
References
4
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 3 · 2015: 1 · 2014: 5 · 2013: 3 · 2012: 1
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of General Physiology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK046409)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
calcium-activated potassium channels, pancreatic beta cells, slow potassium current, ER calcium stores, SERCA, thapsigargin, insulin, extracellular glucose, calcium handling, beta-cell electrical activity, insulin secretion, mathematical modeling
MeSH terms
Action Potentials, Animals, Calcium, Cells, Cultured, Cytoplasm, Endoplasmic Reticulum, Islets of Langerhans, Male, Potassium Channels, Calcium-Activated, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review