Molecular and Cellular Biochemistry

, Volume 190, Issue 1–2, pp 119–124 | Cite as

Roles of intracellular Ca2+ receptors in the pancreatic β-cell in insulin secretion

  • Ichiro Niki
  • Hiroyoshi Hidaka


Ca2+ is the central second messenger in the regulation of insulin release from the pancreatic β-cell; and intracellular Ca2+-binding proteins, classified into two groups, the EF hand proteins and the Ca2+/ phospholipid binding proteins, are considered to mediate Ca2+ signaling. A number of Ca binding proteins have been suggested to participate in the secretory machinery in the β-cell. Calmodulin, the ubiquitous EF hand protein, is the predominant intracellular Ca2+ receptor that modulates insulin release via the multiplicity of its binding to target proteins including protein kinases. Other Ca binding proteins such as calcyclin and the Ca2+/phospholipid binding proteins may also be suggested to be involved. Ca2+ influx from the extracellular space appears to be responsible for exocytosis of insulin via Ca2+-dependent protein/protein interactions. On the other hand, intracellular Ca2+ mobilization resulting in secretory granule movement may be controlled by Ca2+/calmodulin-dependent protein phosphorylation. Thus, Ca2+ exerts versatile effects on the secretory cascade via binding to specific binding proteins in the pancreactic β-cells.

Ca2+ binding proteins secretory granules protein kinases 


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  1. 1.
    Ashcroft FM, Proks P, Smith PA, Ämälä C, Bokvist K, Rorsman P: Stimulus-secretion coupling in pancreatic β cells. J Cell Biol 55S: 54–65, 1994Google Scholar
  2. 2.
    Ebashi S: Ca2+ in biological systems. Experientia 41: 978–981, 1985Google Scholar
  3. 3.
    Schäfer BW, Heizmann CW: The S100 family of EF-hand calcium-binding proteins: Functions and pathology. Trends Biochem Sci 21: 134–140, 199Google Scholar
  4. 4.
    Niki I, Yokokura H, Sudo T, Kato M, Hidaka H: Ca2+ signaling and intracellular Ca binding proteins. J Biochem (Tokyo), 120: 685–698, 1996Google Scholar
  5. 5.
    Kretsinger H: Structure and evolution of calcium-modulated proteins. CRC Crit Rev Biochem 8: 119–174, 1980Google Scholar
  6. 6.
    Sugden MC, Christie MR, Ashcroft SJH: Presence and possible role of calcium-dependent regulator (calmodulin) in rat islets of Langerhans. FEBS Lett 105: 95–100, 1979Google Scholar
  7. 7.
    Krauz Y, Wollheim CB, Siegel E, Sharp GWC: Possible role for calmodulin in insulin release. J Clin Invest 66: 603–607, 1980Google Scholar
  8. 8.
    Niki H, Niki A, Hidaka H: Effects of a new calmodulin inhibitor (W-7) on glucose-induced insulin release and biosynthesis. Biomed Res 2: 413–417, 1981Google Scholar
  9. 9.
    Yaney GC, Sharp GWC: Calmodulin and insulin secretion: Use of naphthalenesulphonamide compounds. Am J Physiol 259: E856–E864, 1990Google Scholar
  10. 10.
    Iida Y, Senda T, Matsukawa Y, Onoda K, Miyazaki J-I, Sakaguchi H, Nimura Y, Hidaka H, Niki I: Myosin light chain phosphorylation controls insulin secretion at a proximal step in the secretory cascade. Am J Physiol 273 (Endocrinol Metab 36): E782–E789, 1997Google Scholar
  11. 11.
    Colca JR, Wolf BA, Comens PG, McDaniel ML: Protein phosphorylation in permeabilized pancreatic islet cells. Biochem J 228: 529–536, 1985Google Scholar
  12. 12.
    Kenigsberg RL, Trifaró JM: Microinjection of calmodulin antibodies into cultured chromatin cells blocks catecholamine release in response to stimulation. Neuroscience 14: 335–347, 1985Google Scholar
  13. 13.
    Valverde I, Vandermeers A, Anjaneyulu R, Malaisse WJ: Calmodulin activation of adenylate cyclase in pancreatic islets. Science 206: 225–227, 1979Google Scholar
  14. 14.
    Patel J, Marangos PJ, Heydorn WE, Chang G, Verma A, Jacobowitz D: S-100-mediated inhibition of brain protein phosphorylation. J Neurochem 41: 1040–1045, 1983Google Scholar
  15. 15.
    Luby-Phelps K, Hori M, Phelps JM, Won D: Ca2+-regulated dynamic compartmentalization of calmodulin in living smooth muscle cells. J Biol Chem 270: 21532–21538, 1995Google Scholar
  16. 16.
    Sharp GWC: The adenylate cyclase-cyclic AMP systeirn in islets of Langerhans and its role in the control of insulin release. Diabetologia 16: 287–296, 1979Google Scholar
  17. 17.
    Ämälä C, Ashcroft FM, Rorsman P: Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells. Nature 363: 356–358, 1993Google Scholar
  18. 18.
    Nairn AC, Picciotto MR: Calcium/calmodulin-dependent protein kinases. Cancer Biol 15: 295–303, 1994Google Scholar
  19. 19.
    Tokumitsu H, Brickey DA, Clod J, Hidaka H, Sikela J, Soderling TR: Activation mechanisms for Ca2+/calmodulin-dependent protein kinase IV. J Biol Chem 269: 28640–28647, 1994Google Scholar
  20. 20.
    Dabrowska R, Aromatorio D, Sherry JMF, Hartshorne DJ: Modulator protein as a component of the myosin light chain kinase from chicken gizzard. Biochemistry 17: 253–258, 1978Google Scholar
  21. 21.
    Penn EJ, Brocklehurst KW, Sopwith AM, Hales CN, Hutton JC: Ca2+-calmodulin-dependent myosin light-chain phosphorylating activity in insulin-secreting tissues. FEBS Lett 139: 4–8, 1982Google Scholar
  22. 22.
    Tan JL, Ravid S, Spudich JA: Control of nonmuscle myosins by phosphorylation. Annu Rev Biochem 61: 721–759, 1992Google Scholar
  23. 23.
    Niki I, Okazaki K, Saitoh M, Niki A, Niki H, Tamagawa T, Iguchi A, Hidaka H: Presence and possible involvement of Ca/calmodulin-dependent protein kinases in insulin release from the rat pancreatic β cell. Biochem Biophys Res Commun 191: 255–261, 1993Google Scholar
  24. 24.
    Kumakura K Sasaki K Sakurai T, Ohara-Imaizumi M, Misonou H, Nakamura S, Matsuda Y, Nonomura Y: Essential role of myosin light chain kinase in the mechanism for MgATP-dependent priming of exocytosis in adrenal chromaffin cells. J Neurosci 14: 7695–7703, 1994Google Scholar
  25. 25.
    Mochida S: Role of myosin in neurotransmitter release: Functional studies at synapses formed in culture. J Physiol (Paris) 89: 83–94, 1995Google Scholar
  26. 26.
    Valtorta F, Benfenati F, Greengard P: Structure and function of the synapsins. J Biol Chem 267: 7195–7198, 1992Google Scholar
  27. 27.
    Matsumoto K, K Fukunaga, J Miyazaki, M Shichiri, E Miyamoto: Ca2+/ calmodulin-dependent protein kinase II and synapsin I-like protein in mouse insulinoma MIN 6 cells. Endocrinology 136: 3784–3793, 1995Google Scholar
  28. 28.
    Hughes SJ, Smith H, Ashcroft SJH: Characterization of Ca2+/ calmodulin-dependent protein kinase in rat pancreatic islets. Biochem J 289: 795–800, 1993Google Scholar
  29. 29.
    Wenham RM, Lancit M, Eason RA: Glucose activates the multifunctional Ca2+/calmodulin-dependent protein kinase II in isolated rat pancreatic islets. J Biol Chem 269: 4947–4952, 1994Google Scholar
  30. 30.
    Pershadsingh HA, McDaniel ML, Landt M, Bry CG, Lacy PE, McDonald JM: Ca2+-activated ATPase and ATP-dependent cal modulin-stimualted Ca2+ transport in islet cell plasma membrane. Nature 288: 492–495, 1980Google Scholar
  31. 31.
    Váradi A, Molnár E, Ashcroft SJH: A unique combination of plasma membrane Ca2+-ATP ase isoforms is expressed in islets of Langerhans and pancreatic β-cell lines. Biochem J 314: 663–669, 1996Google Scholar
  32. 32.
    Watkins D, White BA: Identification and characterization of calmodulin-binding proteins in islet secretion granules. J Biol Chem 260: 5161–5165, 1985Google Scholar
  33. 33.
    Popoli M: Synaptotagmin is endogenously phosphorylated by Ca2+/ calmodulin protein kinase II in synaptic vesicles. FEBS Lett 317: 85–88, 1993Google Scholar
  34. 34.
    Burridge K, Phillips JH: Association of actin and myosin with secretory granule membranes. Nature 254: 526–529, 1975Google Scholar
  35. 35.
    Okazaki K, Niki I, Iino S, Kobayashi S, Hidaka H: A role of calcyclin, a Ca2+-binding protein, on the Ca2+-dependent insulin release from the pancreatic βcell. J Biol Chem 269: 6149–6152, 1994Google Scholar
  36. 36.
    Thordarson G, Southard JN, Talamantes E: Purification and characterization of mouse decidual calcyclin: a novel stimulator of mouse placental lactogen-II secretion. Endocrinology 129: 1257–1265, 1991Google Scholar
  37. 37.
    Glenney JR Jr, Boudreau M, Galyean R, Hunter T, Tack B: Association of the S-100-related calpactin I light chain with the NH2-terminal tail of the 36-kDa heavy chain. J Biol Chem 261: 10485, 1986Google Scholar
  38. 38.
    Mailliard WS, Haigler HT, Schlaepfer DD: Calcium-dependent binding of S100C to the N-terminal domain of annexin I. J Biol Chem 271: 719, 1996Google Scholar
  39. 39.
    Minami H, Tokumitsu H, Mizutani A, Watanabe Y, Watanabe M, Hidaka H: Specific binding of CAP-50 to calcyclin. FEBS Letts. 305: 217–219, 1992Google Scholar
  40. 40.
    Raynal P, Pollard HB: Annexins: The problem of assessing the biological role for a gene family of multifuncitional calcium-and phospholipid-binding proteins. Biochim Biophys Acta 1197: 63–93, 1994Google Scholar
  41. 41.
    Chasserot-Golaz S, Vitale N, Sagot I, Delouche B, Dirrig S, Pradel LA, Henry J-P, Aunis D, Bader M-R: Annexin II in exocytosis: Catecholamine secretion requires the translocation of p36 to the subplasmalemmal region in chromatin cells. J Cell Biol 133: 1217–1236, 1996Google Scholar
  42. 42.
    Caohuy H, Srivatrava M, Pollard HB: Membrane fusion protein synexin (annexin VII) as a Ca2+/ GTP sensor in exocytotic secretion.Google Scholar
  43. 43.
    Ohnishi M, Tokuda M, Masaki T, Fujimura T, Tai Y, Itano T, Matsui H, Ishida T, Konishi R, Takahara J, Hatase O: Involvement of annexin-1 in glucose-induced insulin secretion in rat pancreatic islets. Endocrinology 136: 2421–2426, 1995Google Scholar
  44. 44.
    Tamagawa T, Niki H, Niki A: Insulin release independent of a rise in cytosolic free Ca2+ by forskolin and phorbol ester. FEBS Letts 183: 430–432, 1985Google Scholar
  45. 45.
    Komatsu M, Schermerhorn T, Aizawa T, Sharp GWG: Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets. Proc Natl Acad Sci USA 92: 10728–10732, 1995Google Scholar
  46. 46.
    Malaisse WJ, Sene A: Inhibition by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) of protein kinase C activity and insulin release in pancreatic islets. IRCS Med Sci 13: 1239–1240, 1985Google Scholar
  47. 47.
    Thams P, Capito K, Hedeskov CJ, Kofod H: Phorbol-ester-induced down-regulation of protein kinase C in mouse pancreatic islets. Potentiation of phase 1 and inhibition of phase 2 of glucose-induced insulin release. Biochem J 265: 777–787, 1990Google Scholar
  48. 48.
    Niki I, Tamagawa T, Niki H, Niki A, Koide T, Sakamoto N: (1988) Possible involvement of diacylglycerol-activated, Ca2+-dependent protein kinase in glucose memory of the rat pancreatic B-cell. Acta Endocrinologica (Copenh) 118: 204–208, 1988Google Scholar
  49. 49.
    Hii CS, Jones PM, Persaud SJ, Howell SL: A re-assessment of the role of protein kinase C in glucose-stimulated insulin secretion. Biochem J 246: 489–493, 1987Google Scholar
  50. 50.
    Tian Y-M, Urquidi V, Ashcroft SJH: Protein kinase C in beta-cells: Expression of multiple isoforms and involvement in cholinergic stimulation of insulin secretion. Mol Cell Endocrinol 119: 185–193, 1996Google Scholar
  51. 51.
    Mizuta M, Inagaki N, Nemoto Y, Matsukura S, Takahashi M, Seino S: Synaptotagmin III is a novel isoform of rat synaptotagmin expressed in endocrine and neuronal cells. J Biol Chem 269: 11675–11678, 1994Google Scholar
  52. 52.
    Li C, Ullrich B, Zhang JZ, Anderson RGW, Brose N, Südhof TC: Ca2+-dependent and-independent activities of neural and non-neural synaptotagmins. Nature 375: 594–599, 1995Google Scholar
  53. 53.
    Shirataki H, Kaibuchi K, Sakoda T, Kishida S, Yamaguchi T, Wada K, Miyazaki M, Takai Y: Rabphilin-3A, a putative target protein for smgp25A/rab3A p25 small GTP-binding protein related to synaptotagmin. Mol Cell Biol 13: 2061–2068, 1993Google Scholar
  54. 54.
    Senyshyn J, Balch WE, Holz RW: 1992 Synthetic peptides of the effector-binding domain of rab enhance secretion from digitonin-permeabilized chromaf fin cells. FEBS Letts 309: 41–46, 1992Google Scholar
  55. 55.
    Padfield PJ, Balch WE, Jamieson JD: 1992 A synthetic peptide of the rab3a effector domain stimulates amylase release from permeabilized pancreatic acini. Proc Natl Acad Sci USA 89: 1656–1660, 1992Google Scholar
  56. 56.
    Li G, Regazzi R, Balch WE, Wollheim CB: Stimulation of insulin release from permeabilized HIT-T15 cells by a synthetic peptide corresponding to the effector domains of the small GTP-binding protein rab3. FEBS Letts 327: 145–149, 1993Google Scholar
  57. 57.
    Hisatomi M, Hidaka H, Niki I: Ca2+/ calmodulin and cyclic 3,5′ adenosine monophosphate control movement of secretory granules through protein phosphorylation/dephosphorylation in the pancreatic β-cell. Endocrinology 137: 4644–4649, 1996Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Ichiro Niki
    • 1
  • Hiroyoshi Hidaka
    • 1
  1. 1.Department of PharmacologyNagoya University School of MedicineNagoyaJapan

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