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

Abstract

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 ^K85AGSK3ß. 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 ^K85AGSK3ß. 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.