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.
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