Regulation of glial glutamate transporter expression by growth factors
Regulation of glial glutamate transporter expression by growth factors
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DOI：
10.1016/s0014-4886(03)00134-1
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Engele, J
中科院分区：
文献类型：
--
作者：
Figiel, M;Maucher, T;Engele, J
脑损伤导致神经胶质谷氨酸转运蛋白表达在数小时内下降，几天后恢复。这种紊乱表达的一个后果似乎包括毒性细胞外谷氨酸水平的暂时积累，随后是继发性神经元细胞死亡。虽然有证据表明，谷氨酸转运蛋白表达的下降是由于神经元对星形胶质细胞的PACAP影响的丧失，但诱导胶质谷氨酸转运蛋白重新表达的机制目前尚不清楚。我们现在证明，在培养的皮质星形胶质细胞中，损伤诱导的生长因子EGF、TGFalpha、FGF-2和PDGF都促进谷氨酸转运体GLT-1和/或GLAST的表达。相比之下，不受脑损伤影响的生长因子GDNF和BDNF则没有类似的刺激作用。EGF、TGFalpha、FGF-2和PDGF对神经胶质谷氨酸转运的影响只是部分冗余，并且涉及明显不同的信号通路。与EGF、TGFalpha和FGF-2不同，PDGF促进GLT-1的表达，但不促进GLAST的表达，并且进一步不能增加钠依赖性谷氨酸摄取的最大速度。此外，当RAF-MEK-ERK信号通路同时被PD98059抑制时，FGF-2仅影响胶质谷氨酸转运。根据细胞外生长因子和谷氨酸转运蛋白亚型的不同，观察到的刺激作用需要激活PKA、PKC和/或AKT。我们认为脑损伤后，反应性过程可能通过促进神经胶质谷氨酸转运来限制继发性神经元细胞死亡。对这些代偿机制的详细了解最终将使我们能够在治疗上干扰大脑中谷氨酸相关的神经元细胞死亡。(C) 2003 Elsevier Science（美国）版权所有。
Injuries to the brain result in the decline of glial glutamate transporter expression within hours and a recovery after several days. One consequence of this disturbed expression seems to consist in the temporary accumulation of toxic extracellular glutamate levels followed by secondary neuronal cell death. Whereas evidence exists that the decline in glutamate transporter expression results from a loss of neuronal PACAP influences on astroglia, the mechanism(s) inducing the reexpression of glial glutamate transporters is presently unknown. We now demonstrate that the injury-induced growth factors EGF, TGFalpha, FGF-2, and PDGF all promote the expression of the glutamate transporters GLT-1 and/or GLAST in cultured cortical astroglia. In contrast, similar stimulatory influences were absent with GDNF and BDNF, growth factors not affected by brain injuries. The effects of EGF, TGFalpha, FGF-2, and PDGF on glial glutamate transport were only partly redundant and involved distinctly different signaling pathways. Unlike EGF, TGFalpha, and FGF-2, PDGF promoted GLT-1, but not GLAST expression and further failed to increase the maximal velocity of sodium-dependent glutamate uptake. Moreover, FGF-2 only affected glial glutamate transport when the RAF-MEK-ERK signaling pathway was concomitantly inhibited with PD98059. Depending on the extracellular growth factor and glutamate transporter subtype, the observed stimulatory effects required the activation of PKA, PKC, and/or AKT. We suggest that after brain injury, reactive processes may limit secondary neuronal cell death by promoting glial glutamate transport. The detailed knowledge of these compensatory mechanisms will eventually allow us to therapeutically interfere with glutamate-associated neuronal cell death in the brain. (C) 2003 Elsevier Science (USA). All rights reserved.