Skip to main content
SpringerLink
Log in

CaV1.2 and CaV1.3 channel hyperactivation in mouse islet β cells exposed to type 1 diabetic serum

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The voltage-gated Ca2+ (CaV) channel acts as a key player in β cell physiology and pathophysiology. β cell CaV channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca2+ concentration and thereby Ca2+-triggered β cell apoptosis. The present study was aimed at revealing the subtypes of CaV1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of β cell CaV1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic β cells from CaV1 channel knockout and corresponding control mice. We now show that functional CaV1.3 channels are expressed in a subgroup of islet β cells from CaV1.2 knockout mice (CaV1.2−/−). T1D serum enhanced whole-cell CaV currents in islet β cells from CaV1.3 knockout mice (CaV1.3−/−). T1D serum increased the open probability and number of functional unitary CaV1 channels in CaV1.2−/− and CaV1.3−/− β cells. These data demonstrate that T1D serum hyperactivates both CaV1.2 and CaV1.3 channels by increasing their conductivity and number. These findings suggest CaV1.2 and CaV1.3 channels as potential targets for anti-diabetes therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CaV :

Voltage-gated calcium

CaV1.2−/− :

CaV1.2 subunit knockout

CaV1.3−/− :

CaV1.3 subunit knockout

DHP:

Dihydropyridine

T1D:

Type 1 diabetic

References

  1. Yang SN, Berggren PO (2005) β-Cell CaV channel regulation in physiology and pathophysiology. Am J Physiol 288:E16–E28

    CAS  Google Scholar 

  2. Yang SN, Berggren PO (2006) The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology. Endocr Rev 27:621–676

    Article  CAS  PubMed  Google Scholar 

  3. Trus M, Corkey RF, Nesher R, Richard AM, Deeney JT, Corkey BE, Atlas D (2007) The L-type voltage-gated Ca2+ channel is the Ca2+ sensor protein of stimulus–secretion coupling in pancreatic beta cells. Biochemistry 46:14461–14467

    Article  CAS  PubMed  Google Scholar 

  4. Berggren PO, Yang SN, Murakami M, Efanov AM, Uhles S, Kohler M, Moede T, Fernstrom A, Appelskog IB, Aspinwall CA, Zaitsev SV, Larsson O, Moitoso de Vargas L, Fecher-Trost C, Weissgerber P, Ludwig A, Leibiger B, Juntti-Berggren L, Barker CJ, Gromada J, Freichel M, Leibiger IB, Flockerzi V (2004) Removal of Ca2+ channel β3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell 119:273–284

    Article  CAS  PubMed  Google Scholar 

  5. Yang SN, Shi Y, Yang G, Li Y, Yu J, Berggren PO (2014) Ionic mechanisms in pancreatic β cell signaling. Cell Mol Life Sci. [Epub ahead of print]

  6. Braun M, Ramracheya R, Bengtsson M, Zhang Q, Karanauskaite J, Partridge C, Johnson PR, Rorsman P (2008) Voltage-gated ion channels in human pancreatic β-cells: electrophysiological characterization and role in insulin secretion. Diabetes 57:1618–1628

    Article  CAS  PubMed  Google Scholar 

  7. Iwashima Y, Pugh W, Depaoli AM, Takeda J, Seino S, Bell GI, Polonsky KS (1993) Expression of calcium channel mRNAs in rat pancreatic islets and downregulation after glucose infusion. Diabetes 42:948–955

    Article  CAS  PubMed  Google Scholar 

  8. Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, Obermuller S, Olofsson CS, Salehi A, Wendt A, Klugbauer N, Wollheim CB, Rorsman P, Hofmann F (2003) Impaired insulin secretion and glucose tolerance in β cell-selective CaV1.2 Ca2+ channel null mice. Embo J 22:3844–3854

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, Hering S, Bova S, Rorsman P, Pongs O, Singewald N, Striessnig JJ (2004) Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ channels. J Clin Invest 113:1430–1439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Engel J, Michna M, Platzer J, Striessnig J (2002) Calcium channels in mouse hair cells: function, properties and pharmacology. Adv Otorhinolaryngol 59:35–41

    CAS  PubMed  Google Scholar 

  11. Yang SN, Larsson O, Branstrom R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Kohler M, Meister B, Berggren PO (1999) Syntaxin 1 interacts with the LD subtype of voltage-gated Ca2+ channels in pancreatic β cells. Proc Natl Acad Sci USA 96:10164–10169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, Shin HS (2001) Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation. J Clin Invest 108:1015–1022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Vignali S, Leiss V, Karl R, Hofmann F, Welling A (2006) Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells. J Physiol 572:691–706

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Lee AK, Yeung-Yam-Wah V, Tse FW, Tse A (2011) Cholesterol elevation impairs glucose-stimulated Ca2+ signaling in mouse pancreatic β-cells. Endocrinology 152:3351–3361

    Article  CAS  PubMed  Google Scholar 

  15. Roe MW, Worley JF, Tokuyama Y, Philipson LH, Sturis J, Tang J, Dukes ID, Bell GI, Polonsky KS (1996) NIDDM is associated with loss of pancreatic β-cell L-type Ca2+ channel activity. Am J Physiol 270:E133–E140

    CAS  PubMed  Google Scholar 

  16. Yamada Y, Kuroe A, Li Q, Someya Y, Kubota A, Ihara Y, Tsuura Y, Seino Y (2001) Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients. Diabetes Metab Res Rev 17:213–216

    Article  CAS  PubMed  Google Scholar 

  17. Yamada Y, Masuda K, Li Q, Ihara Y, Kubota A, Miura T, Nakamura K, Fujii Y, Seino S, Seino Y (1995) The structures of the human calcium channel α1 subunit (CACNL1A2) and β subunit (CACNLB3) genes. Genomics 27:312–319

    Article  CAS  PubMed  Google Scholar 

  18. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (2004) CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31

    Article  CAS  PubMed  Google Scholar 

  19. Juntti-Berggren L, Larsson O, Rorsman P, Ammala C, Bokvist K, Wahlander K, Nicotera P, Dypbukt J, Orrenius S, Hallberg A, Berggren PO (1993) Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes. Science 261:86–90

    Article  CAS  PubMed  Google Scholar 

  20. Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, Uhles S, Yu L, Griffiths WJ, Zaitsev S, Leibiger I, Yang SN, Olivecrona G, Jornvall H, Berggren PO (2004) Apolipoprotein CIII promotes Ca2+-dependent β cell death in type 1 diabetes. Proc Natl Acad Sci USA 101:10090–10094

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Shi Y, Yang G, Yu J, Yu L, Westenbroek R, Catterall WA, Juntti-Berggren L, Berggren PO, Yang SN (2014) Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src. Cell Mol Life Sci 71:1289–1303

    Article  CAS  PubMed  Google Scholar 

  22. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, Striessnig J (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102:89–97

    Article  CAS  PubMed  Google Scholar 

  23. Yang SN, Wenna ND, Yu J, Yang G, Qiu H, Yu L, Juntti-Berggren L, Kohler M, Berggren PO (2007) Glucose recruits KATP channels via non-insulin-containing dense-core granules. Cell Metab 6:217–228

    Article  CAS  PubMed  Google Scholar 

  24. Refai E, Dekki N, Yang SN, Imreh G, Cabrera O, Yu L, Yang G, Norgren S, Rossner SM, Inverardi L, Ricordi C, Olivecrona G, Andersson M, Jornvall H, Berggren PO, Juntti-Berggren L (2005) Transthyretin constitutes a functional component in pancreatic β-cell stimulus–secretion coupling. Proc Natl Acad Sci USA 102:17020–17025

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Zhang W, Efanov A, Yang SN, Fried G, Kolare S, Brown H, Zaitsev S, Berggren PO, Meister B (2000) Munc-18 associates with syntaxin and serves as a negative regulator of exocytosis in the pancreatic β-cell. J Biol Chem 275:41521–41527

    Article  CAS  PubMed  Google Scholar 

  26. Yu J, Leibiger B, Yang SN, Caffery JJ, Shears SB, Leibiger IB, Barker CJ, Berggren PO (2003) Cytosolic multiple inositol polyphosphate phosphatase in the regulation of cytoplasmic free Ca2+ concentration. J Biol Chem 278:46210–46218

    Article  CAS  PubMed  Google Scholar 

  27. Brown H, Larsson O, Branstrom R, Yang SN, Leibiger B, Leibiger I, Fried G, Moede T, Deeney JT, Brown GR, Jacobsson G, Rhodes CJ, Braun JEA, Scheller RH, Corkey BE, Berggren PO, Meister B (1998) Cysteine string protein (CSP) is an insulin secretory granule-associated protein regulating β-cell exocytosis. Embo J 17:5048–5058

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Brown H, Meister B, Deeney J, Corkey BE, Yang SN, Larsson O, Rhodes CJ, Seino S, Berggren PO, Fried G (2000) Synaptotagmin III isoform is compartmentalized in pancreatic β-cells and has a functional role in exocytosis. Diabetes 49:383–391

    Article  CAS  PubMed  Google Scholar 

  29. Barg S, Eliasson L, Renstrom E, Rorsman P (2002) A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse β-cells. Diabetes 51:S74–S82

    Article  CAS  PubMed  Google Scholar 

  30. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J (2001) α1D (CaV1.3) Subunits can form L-type Ca2+ channels activating at negative voltages. J Biol Chem 276:22100–22106

    Article  CAS  PubMed  Google Scholar 

  31. Xu W, Lipscombe D (2001) Neuronal CaV1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944–5951

    CAS  PubMed  Google Scholar 

  32. Seino S, Chen L, Seino M, Blondel O, Takeda J, Johnson JH, Bell GI (1992) Cloning of the α1 subunit of a voltage-dependent calcium channel expressed in pancreatic β cells. Proc Natl Acad Sci USA 89:584–588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Herold KC, Vignali DA, Cooke A, Bluestone JA (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243–256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Aguayo-Mazzucato C, Bonner-Weir S (2010) Stem cell therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 6:139–148

    Article  PubMed  Google Scholar 

  35. Lovshin JA, Drucker DJ (2009) Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5:262–269

    Article  CAS  PubMed  Google Scholar 

  36. Lernmark A, Larsson HE (2013) Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol 9:92–103

    Article  CAS  PubMed  Google Scholar 

  37. Lebovitz HE (2011) Type 2 diabetes mellitus–current therapies and the emergence of surgical options. Nat Rev Endocrinol 7:408–419

    Article  CAS  PubMed  Google Scholar 

  38. Holmberg R, Refai E, Höög A, Crooke RM, Graham M, Olivecrona G, Berggren PO, Juntti-Berggren L (2011) Lowering apolipoprotein CIII delays onset of type 1 diabetes. Proc Natl Acad Sci USA 108:10685–10689

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ghazarian L, Diana J, Simoni Y, Beaudoin L, Lehuen A (2013) Prevention or acceleration of type 1 diabetes by viruses. Cell Mol Life Sci 70:239–255

    Article  CAS  PubMed  Google Scholar 

  40. Jahromi MM, Eisenbarth GS (2007) Cellular and molecular pathogenesis of type 1A diabetes. Cell Mol Life Sci 64:865–872

    Article  CAS  PubMed  Google Scholar 

  41. Xu G, Chen J, Jing G, Shalev A (2012) Preventing β-cell loss and diabetes with calcium channel blockers. Diabetes 61:848–856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Ristic H, Srinivasan S, Hall KE, Sima AA, Wiley JW (1998) Serum from diabetic BB/W rats enhances calcium currents in primary sensory neurons. J Neurophysiol 80:1236–1244

    CAS  PubMed  Google Scholar 

  43. Hall KE, Sima AA, Wiley JW (1995) Voltage-dependent calcium currents are enhanced in dorsal root ganglion neurones from the Bio Bred/Worchester diabetic rat. J Physiol 486:313–322

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Hall KE, Sima AA, Wiley JW (1996) Opiate-mediated inhibition of calcium signaling is decreased in dorsal root ganglion neurons from the diabetic BB/W rat. J Clin Invest 97:1165–1172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hall KE, Liu J, Sima AA, Wiley JW (2001) Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy. J Neurophysiol 86:760–770

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Berth von Kantzow’s Foundation, Diabetes Research and Wellness Foundation, EuroDia (FP6-518153), European Research Council (ERC-2013-AdG), the Family Erling-Persson Foundation, Funds of Karolinska Institutet, the Knut and Alice Wallenberg Foundation, Skandia Insurance Company, Ltd., the Stichting af Jochnick Foundation, Strategic Research Program in Diabetes at Karolinska Institutet, the Swedish Diabetes Association, the Swedish Research Council and the Novo Nordisk Foundation. P-OB is the founder of the Biotech Company BioCrine AB and is also a member of the board of this company. S-NY is a consultant to BioCrine AB. Biocrine AB is pursuing ApoCIII as a novel druggable target in diabetes.

Author information

Authors and Affiliations

  1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 171 76, Stockholm, Sweden

    Guang Yang, Yue Shi, Jia Yu, Lina Yu, Lisa Juntti-Berggren, Per-Olof Berggren & Shao-Nian Yang

  2. Jilin Academy of Traditional Chinese Medicine, Changchun, 130021, China

    Guang Yang

  3. National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China

    Yuxin Li & Shao-Nian Yang

  4. Forschergruppe, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802, München, Germany

    Andrea Welling & Franz Hofmann

  5. Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020, Innsbruck, Austria

    Jörg Striessnig

Authors
  1. Guang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lina Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Welling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Franz Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jörg Striessnig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lisa Juntti-Berggren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Per-Olof Berggren
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shao-Nian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Per-Olof Berggren or Shao-Nian Yang.

Additional information

GY and YS contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, G., Shi, Y., Yu, J. et al. CaV1.2 and CaV1.3 channel hyperactivation in mouse islet β cells exposed to type 1 diabetic serum. Cell. Mol. Life Sci. 72, 1197–1207 (2015). https://doi.org/10.1007/s00018-014-1737-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1737-6

Keywords

Search

Navigation