The glial glutamate transporter 1 (GLT1) is expressed by pancreatic β-cells and prevents glutamate-induced β-cell death

Eliana S. Di Cairano, Alberto M. Davalli, Lucia Perego, Silvia Sala, V. Franca Sacchi, Stefano La Rosa, Giovanna Finzi, Claudia Placidi, Carlo Capella, Paola Conti, Victoria E. Centonze, Francesca Casiraghi, Federico Bertuzzi, Franco Folli, Carla Perego

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the α-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal β-cell lines and human islet β-cells but not in α-cells. In human islets, glutamate-induced β-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of β-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced β-cell death, whereas GLT1 up-regulation promoted β-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that β-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

Original languageEnglish (US)
Pages (from-to)14007-14018
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
StatePublished - Apr 22 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Di Cairano, E. S., Davalli, A. M., Perego, L., Sala, S., Sacchi, V. F., La Rosa, S., Finzi, G., Placidi, C., Capella, C., Conti, P., Centonze, V. E., Casiraghi, F., Bertuzzi, F., Folli, F., & Perego, C. (2011). The glial glutamate transporter 1 (GLT1) is expressed by pancreatic β-cells and prevents glutamate-induced β-cell death. Journal of Biological Chemistry, 286(16), 14007-14018. https://doi.org/10.1074/jbc.M110.183517