Pertussis toxin-sensitive modulation of glutamate transport by endothelin-1 type A receptors in glioma cells

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• 作者：Najimi ; Mustapha ; Maloteaux ; Jean-Marie ; Hermans ; Emmanuel
• 关键词：EAAC1 ; neuronal glutamate transporter ; ET-1 ; endothelin-1 ; InsP ; inositol phosphates ; PKC ; protein kinase C ; PI3-K ; phosphatidylinositol 3-kinase ; PLC ; phospholipase C ; PMA ; phorbol 12-myristate 13-acetate ; PTx ; pertussis toxin ; EAAC1 ; Glutamate transport
• 刊名：BBA - Biomembranes
• 出版年：2005
• 出版时间：March 1, 2005
• 年：2005
• 卷：1668
• 期：2
• 页码：195-202
• 全文大小：344 K

文摘

Endothelin-1 (ET-1) is a 21 amino acids peptide that exerts several biological activities through interaction with specific G-protein coupled receptors. Increased ET-1 expression is frequently associated with pathological situations involving alterations in glutamate levels. In the present study, a brief exposure to ET-1 was found to increase aspartate uptake in C6 glioma cells, which endogenously express the neuronal glutamate transporter EAAC1 (pEC₅₀ of 9.89). The stimulatory effect of ET-1 mediated by ET_A receptors corresponds to a 62 % increase in the V_max with no modification of the affinity for the substrate. While protein kinase C activity is known to participate in the regulation of EAAC1, the effect of ET-1 on the glutamate uptake was found to be independent of this kinase activation. In contrast, the inactivation of G_o/i type G-protein dependent signaling with pertussis toxin was found to impair ET-1-mediated regulation of EAAC1. An examination of the cell surface expression of EAAC1 by protein biotinylation studies or by confocal analysis of immuno-fluorescence staining demonstrated that ET-1 stimulates EAAC1 translocation to the cell surface. Hence, the disruption of the cytoskeleton with cytochalasin D prevented ET-1-stimulated aspartate uptake. Together, the data presented in the current study suggest that ET-1 participates in the acute regulation of glutamate transport in glioma cells. Considering the documented role of glutamate excitotoxicity in the development of brain tumors, endothelinergic system constitutes a putative target for the pharmacological control of glutamate transmission at the vicinity of glioma cells.