Gammelsaeter, R;
Coppola, T;
Marcaggi, P;
Storm-Mathisen, J;
Chaudhry, FA;
Attwell, D;
Regazzi, R;
(2011)
A Role for Glutamate Transporters in the Regulation of Insulin Secretion.
PLOS ONE
, 6
(8)
, Article e22960. 10.1371/journal.pone.0022960.
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Abstract
In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from beta-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in beta-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from beta-cells is modulated by the flux of glutamate through the secretory granules.
| Type: | Article |
|---|---|
| Title: | A Role for Glutamate Transporters in the Regulation of Insulin Secretion |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0022960 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0022960 |
| Language: | English |
| Additional information: | © 2011 Gammelsaeter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The work was supported by grants from the Medical Faculty, University of Oslo, the Norwegian Research Council, the Norwegian Diabetes Association, the EU (DECG,QLG3-CT-2001-2004), and the Wellcome Trust (grants 017948 and 075232 to D. Attwell). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | PANCREATIC BETA-CELLS, EXOGENOUS D-ASPARTATE, RAT-BRAIN, VESICULAR GLUTAMATE, DIFFERENTIAL EXPRESSION, NERVE-ENDINGS, AMINO-ACIDS, EXOCYTOSIS, ISLETS, IMMUNOCYTOCHEMISTRY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1318882 |
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