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

  • The ABC of Solute Carriers
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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.

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Notes

  1. Note: capital letters are used for the human “SLC” gene names, whereas lower case “slc” names refer to non-human versions (rodents, etc.)

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  1. Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611, Tokyo, Japan

    Yoshikatsu Kanai

  2. Membrane Biology Program, Renal Division, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA

    Matthias A. Hediger

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Kanai, Y., Hediger, M.A. The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Arch - Eur J Physiol 447, 469–479 (2004). https://doi.org/10.1007/s00424-003-1146-4

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