Glutamate, the major excitatory neurotransmitter, is also present in endocrine pancreatic cells. It is secreted by α-cells and acts as an important signalling molecule to control hormone secretion and β-cell integrity; indeed, chronic exposure to glutamate induces the selective β-cell death by apoptosis and phagocytosis. The extra-cellular glutamate concentration is normally controlled by the high affinity glutamate transporter GLT1/EAAT2. GLT1 electively localizes on β-cell membrane where it modulates hormone release, glutamate clearance and prevents glutamate-induced β-cell death. To understand the role of GLT1 in -cell physiology and pathology, we investigated the effects of acute and chronic high glucose incubations on GLT1 expression, localization and function. In human islets of Langerhans and in mouse β-cells (βTC3) we found that exposure to high glucose did not significantly affect the total GLT1 expression but caused its relocalization in intracellular vesicular compartments. The result was confirmed by means of [3H]D-glutamate uptake experiments and by TIRF microscopy on βTC3 cells transfected with the GFP-tagged-GLT1 transporter. We used western blotting analyses to demonstrate the selective involvement of the PI3K/Akt in the GLT1 modulation. By means of uptake experiments using specific pharmacological inhibitors, we confirmed the role of PI3K/Akt and also PKC pathways in GLT1 regulation and we excluded the involvement of MAP/MEK, tyrosine kinase and PKA pathways. Understanding the molecular mechanisms that modulate glutamate release and clearance in islet of Langerhans may be important to control glucose homeostasis in health and disease.

Signaling pathways responsible for the regulation of the glutamate transporter 1 (GLT1/EAAT2) in pancreatic beta cells / S. Moretti, E. Di Cairano, F. Bertuzzi, F. Folli, C. Perego. ((Intervento presentato al 29. convegno Italian Physiological Society (SIF) : Annual Meeting of Young Researchers. tenutosi a Firenze nel 2014.

Signaling pathways responsible for the regulation of the glutamate transporter 1 (GLT1/EAAT2) in pancreatic beta cells

S. Moretti
Primo
;
E. Di Cairano
Secondo
;
F. Folli
Penultimo
;
C. Perego
Ultimo
2014

Abstract

Glutamate, the major excitatory neurotransmitter, is also present in endocrine pancreatic cells. It is secreted by α-cells and acts as an important signalling molecule to control hormone secretion and β-cell integrity; indeed, chronic exposure to glutamate induces the selective β-cell death by apoptosis and phagocytosis. The extra-cellular glutamate concentration is normally controlled by the high affinity glutamate transporter GLT1/EAAT2. GLT1 electively localizes on β-cell membrane where it modulates hormone release, glutamate clearance and prevents glutamate-induced β-cell death. To understand the role of GLT1 in -cell physiology and pathology, we investigated the effects of acute and chronic high glucose incubations on GLT1 expression, localization and function. In human islets of Langerhans and in mouse β-cells (βTC3) we found that exposure to high glucose did not significantly affect the total GLT1 expression but caused its relocalization in intracellular vesicular compartments. The result was confirmed by means of [3H]D-glutamate uptake experiments and by TIRF microscopy on βTC3 cells transfected with the GFP-tagged-GLT1 transporter. We used western blotting analyses to demonstrate the selective involvement of the PI3K/Akt in the GLT1 modulation. By means of uptake experiments using specific pharmacological inhibitors, we confirmed the role of PI3K/Akt and also PKC pathways in GLT1 regulation and we excluded the involvement of MAP/MEK, tyrosine kinase and PKA pathways. Understanding the molecular mechanisms that modulate glutamate release and clearance in islet of Langerhans may be important to control glucose homeostasis in health and disease.
24-mag-2014
GLT1/EAAT2; diabetes; PI3K/AKT; islets of langerhans
Settore BIO/09 - Fisiologia
Signaling pathways responsible for the regulation of the glutamate transporter 1 (GLT1/EAAT2) in pancreatic beta cells / S. Moretti, E. Di Cairano, F. Bertuzzi, F. Folli, C. Perego. ((Intervento presentato al 29. convegno Italian Physiological Society (SIF) : Annual Meeting of Young Researchers. tenutosi a Firenze nel 2014.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/252477
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