title: The glial glutamate transporter 1 (GLT1) is expressed by pancreatic beta-cells and prevents glutamate-induced beta-cell death.
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.
authors.affiliation: Department of Molecular Science Applied to Biosystems, Università degli Studi di Milano, 20134 Milan, Italy.
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Di Cairano
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Davalli
authors.forename: Lucia
authors.initials: L
authors.lastname: Perego
authors.forename: Silvia
authors.initials: S
authors.lastname: Sala
authors.forename: V Franca
authors.initials: VF
authors.lastname: Sacchi
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Placidi
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Centonze
authors.forename: Francesca
authors.initials: F
authors.lastname: Casiraghi
authors.forename: Federico
authors.initials: F
authors.lastname: Bertuzzi
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Carla
authors.initials: C
authors.lastname: Perego
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002470:Cell Survival; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000502:physiology; D005786:Gene Expression Regulation; D050491:Glutamate Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000502:physiology; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; C493396:Slc1a2 protein, mouse; D018698:Glutamic Acid