Up-Regulation of Excitatory Amino Acid Transporters EAAT3 and EAAT4 by Lithium Sensitive Glycogen Synthase Kinase GSK3ß

Background: Cellular uptake of glutamate by the excitatory amino-acid transporters (EAATs) decreases excitation and thus participates in the regulation of neuroexcitability. Kinases impacting on neuronal function include Lithium-sensitive glycogen synthase kinase GSK3ß. The present study thus explored whether the activities of EAAT3 and/or EAAT4 isoforms are sensitive to GSK3ß. Methods: cRNA encoding wild type EAAT3 (SLC1A1) or EAAT4 (SLC1A6) was injected into Xenopus oocytes without or with additional injection of cRNA encoding wild type GSK3ß or the inactive mutant K85A GSK3ß. Dual electrode voltage clamp was performed in order to determine glutamate-induced current (I EAAT ). Results: Appreciable I EAAT was observed in EAAT3 or EAAT4 expressing but not in water injected oocytes. I EAAT was significantly increased by coexpression of GSK3ß but not by coexpression of K85A GSK3ß. Coexpression of GSK3ß increased significantly the maximal I EAAT in EAAT3 or EAAT4 expressing oocytes, without significantly modifying apparent affinity of the carriers. Lithium (1 mM) exposure for 24 hours decreased I EAAT in EAAT3 and GSK3ß expressing oocytes to values similar to I EAAT in oocytes expressing EAAT3 alone. Lithium did not significantly modify I EAAT in oocytes expressing EAAT3 without GSK3ß. Conclusions: Lithium-sensitive GSK3ß is a powerful regulator of excitatory amino acid transporters EAAT3 and EAAT4.