Downregulation of the Creatine Transporter SLC6A8 by JAK2

Downregulation of the Creatine Transporter SLC6A8 by JAK2 Janus-activated kinase-2 (JAK2) participates in the regulation of the Na+-coupled glucose transporter SGLT1 and the Na+-coupled amino acid transporter SLC6A19. Concentrative cellular creatine uptake is similarly accomplished by Na+-coupled transport. The carrier involved is SLC6A8 (CreaT). The present study thus explored whether JAK2 regulates the activity of SLC6A8. To this end, cRNA encoding SLC6A8 was injected into Xenopus oocytes with or without cRNA encoding wild-type JAK2, constitutively active V617FJAK2 or inactive K882EJAK2. Electrogenic creatine transport was determined in those oocytes by dual-electrode voltage-clamp experiments. In oocytes injected with cRNA encoding SLC6A8 but not in oocytes injected with water or with cRNA encoding JAK2 alone, addition of 1 mM creatine to the extracellular bath generated an inward current (I crea). In SLC6A8 expressing oocytes I crea was significantly decreased by coexpression of JAK2 or V617FJAK2 but not by coexpression of K882EJAK2. According to kinetic analysis, coexpression of JAK2 decreased the maximal transport rate without significantly modifying the affinity of the carrier. In oocytes expressing SLC6A8 and V617FJAK2 I crea was gradually increased by the JAK2 inhibitor AG490 (40 μM). In SLC6A8 and JAK2 coexpressing oocytes the decline of I crea following disruption of carrier insertion with brefeldin A (5 μM) was similar in the absence and presence of JAK2. In conclusion, JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Downregulation of the Creatine Transporter SLC6A8 by JAK2

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Publisher
Springer-Verlag
Copyright
Copyright © 2012 by Springer Science+Business Media, LLC
Subject
Life Sciences; Human Physiology; Biochemistry, general
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-012-9424-8
Publisher site
See Article on Publisher Site

Abstract

Janus-activated kinase-2 (JAK2) participates in the regulation of the Na+-coupled glucose transporter SGLT1 and the Na+-coupled amino acid transporter SLC6A19. Concentrative cellular creatine uptake is similarly accomplished by Na+-coupled transport. The carrier involved is SLC6A8 (CreaT). The present study thus explored whether JAK2 regulates the activity of SLC6A8. To this end, cRNA encoding SLC6A8 was injected into Xenopus oocytes with or without cRNA encoding wild-type JAK2, constitutively active V617FJAK2 or inactive K882EJAK2. Electrogenic creatine transport was determined in those oocytes by dual-electrode voltage-clamp experiments. In oocytes injected with cRNA encoding SLC6A8 but not in oocytes injected with water or with cRNA encoding JAK2 alone, addition of 1 mM creatine to the extracellular bath generated an inward current (I crea). In SLC6A8 expressing oocytes I crea was significantly decreased by coexpression of JAK2 or V617FJAK2 but not by coexpression of K882EJAK2. According to kinetic analysis, coexpression of JAK2 decreased the maximal transport rate without significantly modifying the affinity of the carrier. In oocytes expressing SLC6A8 and V617FJAK2 I crea was gradually increased by the JAK2 inhibitor AG490 (40 μM). In SLC6A8 and JAK2 coexpressing oocytes the decline of I crea following disruption of carrier insertion with brefeldin A (5 μM) was similar in the absence and presence of JAK2. In conclusion, JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane.

Journal

The Journal of Membrane BiologySpringer Journals

Published: Mar 11, 2012

References

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