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Regulation of the Glutamate Transporter EAAT2 by PIKfyve

机译：PIKfyve对谷氨酸转运蛋白EAAT2的调节

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摘要

The Na+, glutamate cotransporter EAAT2 is expressed in astrocytes and clears glutamate from the synaptic cleft. EAAT2 dependent currrent is stimulated by the serum and glucocorticoid inducible kinase SGK1. Phosphorylation targets of SGK1 include the human phosphatidylinositol-3-phosphate-5-kinase PIKfyve (PIP5K3). Nothing is known, however, on the role of PIKfyve in the regulation of EAAT2. The present experiments thus explored, whether PIKfyve expression modifies EAAT2 dependent currrent and protein abundance in the cell membrane. In Xenopus oocytes expressing EAAT2 but not in water injected oocytes application of glutamate (2 mM) induced an inward current (I-glu). Coexpression of either, SGK1 or PIKfyve, significantly enhanced I-glu in EAAT2 expressing oocytes. I-glu was significantly higher in Xenopus oocytes coexpressing EAAT2, SGK1 and PIKfyve than in Xenopus oocytes expressing EAAT2 and either, SGK1 or PIKfyve, alone. Additional coexpression of the inactive mutant of the serum and glucocorticoid inducible kinase (K127N)SGK1 did not significantly alter I-glu in EAAT2 expressing oocytes and significantly decreased I-glu in oocytes coexpressing EAAT2 together with PIKfyve. The stimulating effect of PIKfyve on I-glu was abrogated by replacement of the serine in the SGK consensus sequence by alanine ((S318A)PIKfyve). Furthermore, additional coexpression of (S318A)PIKfyve virtually abolished I-glu in Xenopus oocytes coexpressing SGK1 and EAAT2. Confocal microscopy reveals that PIKfyve enhances the EAAT2 protein abundance in the cell membrane. The observations disclose that PIKfyve indeed participates in the regulation of EAAT2.
机译：Na +，谷氨酸共转运蛋白EAAT2在星形胶质细胞中表达，并清除突触间隙中的谷氨酸。血清和糖皮质激素诱导激酶SGK1刺激EAAT2依赖的电流。 SGK1的磷酸化靶标包括人磷脂酰肌醇-3-磷酸-5-激酶PIKfyve（PIP5K3）。但是，关于PIKfyve在EAAT2调控中的作用一无所知。因此，本实验探索了PIKfyve表达是否修饰了细胞膜中EAAT2依赖的电流和蛋白质丰度。在表达EAAT2的非洲爪蟾卵母细胞中，但在注水卵母细胞中不表达，应用谷氨酸（2 mM）诱导内向电流（I-glu）。 SGK1或PIKfyve的共表达显着增强了表达EAAT2的卵母细胞中的I-glu。共表达EAAT2，SGK1和PIKfyve的非洲爪蟾卵母细胞中I-glu明显高于单独表达EAAT2和SGK1或PIKfyve的爪蟾卵母细胞。血清和糖皮质激素诱导激酶（K127N）SGK1的失活突变体的其他共表达不会显着改变表达EAAT2的卵母细胞中的I-glu，并且不会显着降低共表达EAAT2和PIKfyve的卵母细胞中的I-glu。通过用丙氨酸（（S318A）PIKfyve）替代SGK共有序列中的丝氨酸，可以消除PIKfyve对I-glu的刺激作用。此外，（S318A）PIKfyve的额外共表达实际上消除了共表达SGK1和EAAT2的非洲爪蟾卵母细胞中的I-glu。共聚焦显微镜显示PIKfyve增强了细胞膜中EAAT2蛋白的丰度。观察结果表明，PIKfyve确实参与了EAAT2的监管。

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