Regulation of the Glutamate Transporters by JAK2

Cellular Physiology and Biochemistry

关键词: Astrocytes;    Neuroexcitability;    Neurotransmission;    Excitatory amino acid transporter;    Leptin;    Erythropoietin;   

DOI  :  10.1159/000335763

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

The Janus-activated kinase-2 JAK2 is involved in the signaling of leptin and erythropoietin receptors andmediates neuroprotective effects of the hormones. In theory, JAK2 could be effective through modulation of the glutamate transporters, carriers accounting for the clearance of glutamate released during neurotransmission. The present study thus elucidated the effect of JAK2 on the glutamate transporters EAAT1, EAAT2, EAAT3 and EAAT4. To this end, cRNA encoding the carriers was injected into Xenopus oocytes with or without cRNA encoding JAK2 and glutamate transport was estimated from glutamate induced current (I_glu). I_glu was observed in Xenopus oocytes expressing EAAT1 or EAAT2 or EAAT3 or EAAT4, but not in water injected oocytes. Coexpression of JAK2 resulted in an increase of I_glu by 83% (EAAT1), 67% (EAAT2), 42% (EAAT3) and 126% (EAAT4). As shown for EAAT4 expressing Xenopus oocytes, the effect of JAK2 was mimicked by gain of function mutation ^V617FJAK2 but not by the inactive mutant ^K882EJAK2. Incubation with JAK2 inhibitor AG490 (40 µM) resulted in a gradual decrease of I_glu by 53%, 79% and 92% within 3, 6 and 24 hours. Confocal microscopy and chemiluminescence analysis revealed that JAK2 coexpression increased EAAT4 protein abundance in the cell membrane. Disruption of transcription did not appreciably modify the up-regulation of I_glu in EAAT4 expressing oocytes. The decay of I_glu following inhibition of carrier insertion with brefeldin A was similar in oocytes expressing EAAT4 + JAK2 and oocytes expressing EAAT4 alone, indicating that JAK2 did not appreciably affect carrier retrieval from the membrane. In conclusion, JAK2 is a novel powerful regulator of glutamate transporters and thus participates in the protection against excitotoxicity.

【 授权许可】

CC BY-NC-ND