Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes.
Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes.
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DOI：
10.1016/j.ejphar.2011.12.015
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发表时间：
2012-02-29
影响因子：
5
通讯作者：
Hayashida, Ken-ichiro
中科院分区：
文献类型：
--
作者：
Yoshizumi, Masaru;Eisenach, James C.;Hayashida, Ken-ichiro
我们最近证明，谷氨酸转运蛋白激动剂利鲁唑矛盾地促进了谷氨酸诱导的培养星形胶质细胞释放谷氨酸。我们进一步证明了利鲁唑和α-2δ亚单位配体加巴喷丁通过增加蓝斑谷氨酸受体信号来激活大鼠下行抑制，并假设这两种药物有共同的促进星形胶质细胞释放谷氨酸的机制。在本研究中，我们研究了利鲁唑和加巴喷丁对原代培养的星形胶质细胞谷氨酸摄取和释放以及谷氨酸诱导的钙反应的影响。利鲁唑和加巴喷丁促进谷氨酸诱导的星形胶质细胞释放谷氨酸，并显著增加谷氨酸摄取，后者可被非选择性谷氨酸转运体阻滞剂DL-苏氨酸-β-苄氧天冬氨酸(DL-TBOA)完全阻断。利鲁唑和加巴喷丁也能增强谷氨酸诱导的细胞内钙离子浓度升高。普瑞巴林和L异亮氨酸能增强谷氨酸诱导的钙反应，而3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic酸(αδ，ABHCA)则不能。利鲁唑和加巴喷丁对谷氨酸诱导的细胞内钙反应的增强作用可被DL-TBOA和钠/钙交换抑制剂2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea(KB-R7943)阻断。加巴喷丁对钙升高的促进作用是谷氨酸刺激所特有的，因为它不能被三磷酸腺苷刺激所模拟。这些结果表明，利鲁唑和加巴喷丁通过谷氨酸转运体促进Na+-谷氨酸的共转运，通过反向Na+/Ca~(2+)交换方式诱导随后的Ca~(2+)内流，从而促进星形胶质细胞谷氨酸依赖的谷氨酸释放。本研究还证明了除了神经元中的α2δ亚单位外，在星形胶质细胞中还有一个新的加巴喷丁作用靶点。
We have recently demonstrated that the glutamate transporter activator riluzole paradoxically enhanced glutamate-induced glutamate release from cultured astrocytes. We further showed that both riluzole and the α2δ subunit ligand gabapentin activated descending inhibition in rats by increasing glutamate receptor signaling in the locus coeruleus and hypothesized that these drugs share common mechanisms to enhance glutamate release from astrocytes. In the present study, we examined the effects of riluzole and gabapentin on glutamate uptake and release and glutamate-induced Ca2+ responses in primary cultures of astrocytes. Riluzole and gabapentin facilitated glutamate-induced glutamate release from astrocytes and significantly increased glutamate uptake, the latter being completely blocked by the non-selective glutamate transporter blocker DL-threo-β-benzyloxyaspartic acid (DL-TBOA). Riluzole and gabapentin also enhanced the glutamate-induced increase in intracellular Ca2+ concentrations. Some α2δ subunit ligands, pregabalin and L-isoleucine, enhanced the glutamate-induced Ca2+ response, whereas another, 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA), did not. The enhancement of glutamate-induced intracellular Ca2+ response by riluzole and gabapentin was blocked by the DL-TBOA and an inhibitor of Na+/Ca2+ exchange, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943). Gabapentin’s enhancement of Ca2+ increase was specific to glutamate stimulation, as it was not mimicked with stimulation by ATP. These results suggest that riluzole and gabapentin enhance Na+-glutamate co-transport through glutamate transporters, induce subsequent Ca2+ influx via the reverse mode of Na+/Ca2+ exchange, and thereby facilitate Ca2+-dependent glutamate release by glutamate in astrocytes. The present study also demonstrates a novel target of gabapentinoid action in astrocytes other than α2δ subunits in neurons.
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影响因子：
8.8
作者：
Hayashida, Ken-ichiro;Obata, Hideaki;Eisenach, James C.
通讯作者：
Eisenach, James C.
影响因子：
4.8
作者：
Gee, NS;Brown, JP;Woodruff, GN
通讯作者：
Woodruff, GN
影响因子：
4.2
作者：
Hansson, E;Muyderman, H;Rönnbäck, L
通讯作者：
Rönnbäck, L
影响因子：
4.7
作者：
Rojas, Hector;Colina, Claudia;DiPolo, Reinaldo
通讯作者：
DiPolo, Reinaldo
影响因子：
4.2
作者：
Kimelberg, HK;Cai, Z;Zhou, M
通讯作者：
Zhou, M