ASCT1

ASCT1 (Alanine/Serine/Cysteine/Threonine-preferring Transporter 1)

Aliases: SATT, SPATCCM, Neutral Amino Acid Transporter A

Gene name: Solute carrier family 1 member 4 (SLC1A4)

A multitude of membrane transporters are involved in the uptake of amino acids into cells. Amino acid transporters are very diverse in terms of both substrates and localization, although some display partly overlapping substrate specificities. One of the earliest discovered amino acid transport systems, named ASC, is found in almost all somatic cells and mainly transports small neutral zwitterionic amino acids such as alanine, serine, cysteine, and threonine in a sodium-dependent manner. Two important members of the ASC system are the ubiquitously expressed ASCT1 (SLC1A4) and ASCT2 (SLC1A5), whose 40% sequence similarity reflects their common origin and explains the partial overlap of their substrates (Zerangue & Kavanaugh, 1996; Pinilla-Tenas et al., 2003).

ASCT1 is highly expressed in skeletal muscle, lung, kidneys, ovaries, heart, and the digestive system. It is also widely expressed in the brain, with pronounced presence in glial cells such as astrocytes but no evidence of expression in the blood-brain barrier. Although the physiological role of ASCT1 has not yet been entirely elucidated, it is thought to contribute to brain metabolism, as well as neural development and differentiation (Scalise et al., 2021). Its best-characterized functions are related to the maintenance of cerebral neurotransmitter homeostasis. It transports L- and D-serine as gliotransmitters in astrocytes. It also plays an important role in taking back cysteine ​​and controlling amino acid levels in the brain, thus preventing cytotoxicity (Kaplan et al., 2018; Arriza et al., 1993; Yamamoto et al., 2003). Since ASCT1 also recognizes D-amino acids, including D-serine, which is a coagonist of the N-methyl D-aspartate (NMDA) -type glutamate receptor, it plays a critical role in neurotransmission and modulation (Foster et al., 2016). The aforementioned functions are also confirmed by pathological conditions associated with ASCT1 dysfunction, such as altered brain development and microcephaly, schizophrenia, visual disturbances, and amyotrophic lateral sclerosis (ALS) (Scalise et al., 2021; Kaplan et al., 2018; Li et al., 2018; El-Hattab, 2016).

Although selective and potent inhibitors of ASCT1 and 2 have been identified and are being sought after, no currently approved drug is known to interfere with ASCT1 function, and the FDA or EMA guidelines contain no recommendations on testing interactions of novel chemical entities with ASCT1.

References

Arriza JL, Kavanaugh MP, Fairman WA, Wu YN, Murdoch GH, North RA, Amara SG. Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J Biol Chem. 1993 Jul 25;268(21):15329-32. PMID: 8101838.

El-Hattab AW. Serine biosynthesis and transport defects. Mol Genet Metab. 2016 Jul;118(3):153-159. doi: 10.1016/j.ymgme.2016.04.010. Epub 2016 Apr 22. PMID: 27161889.

Foster AC, Farnsworth J, Lind GE, Li YX, Yang JY, Dang V, Penjwini M, Viswanath V, Staubli U, Kavanaugh MP. D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. PLoS One. 2016 Jun 7;11(6):e0156551. doi: 10.1371/journal.pone.0156551. PMID: 27272177; PMCID: PMC4896441.

Kaplan E, Zubedat S, Radzishevsky I, Valenta AC, Rechnitz O, Sason H, Sajrawi C, Bodner O, Konno K, Esaki K, Derdikman D, Yoshikawa T, Watanabe M, Kennedy RT, Billard JM, Avital A, Wolosker H. ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment. Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9628-9633. doi: 10.1073/pnas.1722677115. Epub 2018 Sep 5. PMID: 30185558; PMCID: PMC6156681.

Li YX, Yang JY, Alcantara M, Abelian G, Kulkarni A, Staubli U, Foster AC. Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction. J Pharmacol Exp Ther. 2018 Nov;367(2):292-301. doi: 10.1124/jpet.118.251116. Epub 2018 Aug 31. PMID: 30171039.

Pinilla-Tenas J, Barber A, Lostao MP. Transport of proline and hydroxyproline by the neutral amino-acid exchanger ASCT1. J Membr Biol. 2003 Sep 1;195(1):27-32. doi: 10.1007/s00232-003-2041-9. PMID: 14502423.

Scalise M, Console L, Cosco J, Pochini L, Galluccio M, Indiveri C. ASCT1 and ASCT2: Brother and Sister? SLAS Discov. 2021 Oct;26(9):1148-1163. doi: 10.1177/24725552211030288. Epub 2021 Jul 16. PMID: 34269129.

Yamamoto T, Nishizaki I, Furuya S, Hirabayashi Y, Takahashi K, Okuyama S, Yamamoto H. Characterization of rapid and high-affinity uptake of L-serine in neurons and astrocytes in primary culture. FEBS Lett. 2003 Jul 31;548(1-3):69-73. doi: 10.1016/s0014-5793(03)00742-7. PMID: 12885409.

Zerangue N, Kavanaugh MP. ASCT-1 is a neutral amino acid exchanger with chloride channel activity. J Biol Chem. 1996 Nov 8;271(45):27991-4. doi: 10.1074/jbc.271.45.27991. PMID: 8910405.