The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects

Abstract

The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

“…Consistent alterations in the expression of glutamate transporter genes suggest major involvement of neuroglia in the pathology of depression, whereas changes in expression of certain GABA A receptor subunit genes in suicide victims from both MDD and BPD suggest their value as potential biomarkers for predicting suicidal behavior in both affective disorders. The glial high-affinity glutamate transporters SLC1A2 and SLC1A3 are members of SLC1, a seven-member family of amino acid transporters (22)(23)(24). SLC1A2 and SLC1A3 are primarily astroglial in distribution (25).…”

Inactivation by Hg2+ and methylmercury of the glutamine/amino acid transporter (ASCT2) reconstituted in liposomes: Prediction of the involvement of a CXXC motif by homology modelling

“…As it was previously reported, ASCT2 belongs to the transporter family SLC1. This family includes also ASCT1 and EAAT1 [39], which are homologue of the glutamate transporter Glt Ph , whose structure was resolved by X-ray…”

“…The implication of the mechanisms of inhibition of the ASCT2 transporter in toxicology may be relevant since this transport system plays important functions in several districts among which the intestine, kidney and nervous tissue [39][40]. The inhibitory effects have been observed at concentrations far below the LD 50 of mercuric reagents [1].…”

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

“…16 These transporters exhibit 44-55% similarity at the amino acid level. 17,18 Pharmacologically, EAAT2 differs from other members of the family in that it is inhibited by dihydrokainate and kainate, whereas the other transporters are not. 19 In recent years, progress has been made in identifying compounds that selectively inhibit EAAT2 without blocking the other high-affinity glutamate transporters.…”