Janus kinase 3 (JAK3) contributes to cytokine receptor signaling, confers cell survival and stimulates cell proliferation. The gain of function mutation JAK3A572V is found in acute megakaryoplastic leukemia. Replacement of ATP coordinating lysine by alanine yields inactive JAK3K855A. Most recent observations revealed the capacity of JAK3 to regulate ion transport. This study thus explored whether JAK3 regulates glutamate transporters EAAT1-4, carriers accomplishing transport of glutamate and aspartate in a variety of cells including intestinal cells, renal cells, glial cells, and neurons. To this end, EAAT1, 2, 3, or 4 were expressed in Xenopus oocytes with or without additional expression of mouse wild-type JAK3, constitutively active JAK3A568V or inactive JAK3K851A, and electrogenic glutamate transport was determined by dual electrode voltage clamp. Moreover, Ussing chamber was employed to determine electrogenic glutamate transport in intestine from mice lacking functional JAK3 (jak3 −/−) and from corresponding wild-type mice (jak3 +/+). As a result, in EAAT1, 2, 3, or 4 expressing oocytes, but not in oocytes injected with water, addition of glutamate to extracellular bath generated an inward current (I g), which was significantly increased following coexpression of JAK3. I g in oocytes expressing EAAT3 was further increased by JAK3A568V but not by JAK3K851A. I g in EAAT3 + JAK3 expressing oocytes was significantly decreased by JAK3 inhibitor WHI-P154 (22 µM). Kinetic analysis revealed that JAK3 increased maximal I g and significantly reduced the glutamate concentration required for half maximal I g (K m). Intestinal electrogenic glutamate transport was significantly lower in jak3 −/− than in jak3 +/+ mice. In conclusion, JAK3 is a powerful regulator of excitatory amino acid transporter isoforms.
The Journal of Membrane Biology – Springer Journals
Published: Jun 14, 2014
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