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R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion

Nature Cell Biology volume 9, pages 453–460 (2007)Cite this article

Abstract

Pancreatic islets have a central role in blood glucose homeostasis. In addition to insulin-producing β-cells and glucagon-secreting α-cells, the islets contain somatostatin-releasing δ-cells1. Somatostatin is a powerful inhibitor of insulin and glucagon secretion2. It is normally secreted in response to glucose3 and there is evidence suggesting its release becomes perturbed in diabetes4. Little is known about the control of somatostatin release. Closure of ATP-regulated K+-channels (KATP-channels)5 and a depolarization-evoked increase in cytoplasmic free Ca2+ concentration ([Ca2+]i)6,7,8 have been proposed to be essential. Here, we report that somatostatin release evoked by high glucose (≥10 mM) is unaffected by the KATP-channel activator diazoxide and proceeds normally in KATP-channel-deficient islets. Glucose-induced somatostatin secretion is instead primarily dependent on Ca2+-induced Ca2+-release (CICR). This constitutes a novel mechanism for KATP-channel-independent metabolic control of pancreatic hormone secretion.

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Figure 1: Late component of exocytosis in pancreatic δ-cells.
Figure 2: CICR-regulated exocytosis in pancreatic δ-cells.
Figure 3: [Ca2+]i continues to increase following the pulse in δ-cells.
Figure 4: Somatostatin secretion, KATP-channels, R-type Ca2+-channels and CICR.

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Acknowledgements

We thank M. A. Magnuson (Vanderbilt University) for supplying the SUR1-deficient mice. This work is supported by the Wellcome Trust, DiabetesUK and the European Union (Biosim, LSHB-CT-2004-005137; and Eurodia, SHM-CT-2006-518153). F.M.A. is a Royal Society Research Professor and P.R. is a Royal Society Wolfson Merit Award Research Fellow.

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Authors and Affiliations

  1. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK

    Quan Zhang, Chris Partridge, Matthias Braun & Patrik Rorsman

  2. Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, SE20502, Sweden

    Quan Zhang, Martin Bengtsson, Albert Salehi, Lena Eliasson & Erik Renström

  3. MRC Mammalian Genetics Unit, Medical Research Council, Harwell, OX11 0RD, Didcot, UK

    Roger Cox

  4. Nuffield Department of Surgery, Level 6, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Paul RV Johnson

  5. Institute of Neurophysiology, University of Cologne, Robert-Koch-Str. 39, Köln, D-50931, Germany

    Toni Schneider

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

    Per-Olof Berggren

  7. AstraZeneca R&D, Pepparedsleden 1, Mölndal, SE-43183, Sweden

    Sven Göpel

  8. Department of Physiology, Anatomy and Genetics, Parks Road, University of Oxford, Oxford, OX1 3PT, UK

    Frances M Ashcroft

Authors
  1. Quan Zhang
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Contributions

Q.Z. performed most of the electrophysiological experiments, including those involving microfluorimetry and confocal imaging. C.P. performed all immunocytochemistry. S.G. participated in the early stages of the electrophysiological experiments were also performed by M. Braun. The PCR analyses were performed by M. Bengtsson. The hormone release measurements were performed by A.S. P.O.B., R.C., E.R. and T.S. provided SUR1−/−, Kir6.2STOP, and Cav2.3−/−, respectively. P.R.V.J. provided human islet cells (data not shown). L.E. analysed δ-cell ultrastructure using electron microscopy. F.M.A. contributed to the discussion of the data throughout the study and assisted with manuscript preparation. The study was initiated by P.R. who directed all experimental protocols used, performed some of the electrophysiological measurements, liaised with all co-authors and was the main author of the manuscript.

Corresponding author

Correspondence to Patrik Rorsman.

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The authors declare no competing financial interests.

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Supplementary figures S1, S2, S3 and S4 (PDF 649 kb)

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Zhang, Q., Bengtsson, M., Partridge, C. et al. R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion. Nat Cell Biol 9, 453–460 (2007). https://doi.org/10.1038/ncb1563

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