8cv2

Structural highlights

Disease

EAA3_HUMAN Hot water reflex epilepsy;Dicarboxylic aminoaciduria. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099).^{[1] [2]}

Function

EAA3_HUMAN Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7914198, PubMed:7521911, PubMed:8857541, PubMed:26690923, PubMed:21123949, PubMed:33658209). Can also transport L-cysteine (PubMed:21123949). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:7521911, PubMed:8857541, PubMed:26690923, PubMed:33658209). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:8857541, PubMed:26690923). Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli (PubMed:21123949). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity). Contributes to glutathione biosynthesis and protection against oxidative stress via its role in L-glutamate and L-cysteine transport (By similarity). Negatively regulated by ARL6IP5 (By similarity).[UniProtKB:P51906][UniProtKB:P51907]^{[3] [4] [5] [6] [7] [8]}

References

1. ↑ Melhem N, Middleton F, McFadden K, Klei L, Faraone SV, Vinogradov S, Tiobech J, Yano V, Kuartei S, Roeder K, Byerley W, Devlin B, Myles-Worsley M. Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees. Biol Psychiatry. 2011 Dec 15;70(12):1115-21. PMID:21982423 doi:10.1016/j.biopsych.2011.08.009
2. ↑ Myles-Worsley M, Tiobech J, Browning SR, Korn J, Goodman S, Gentile K, Melhem N, Byerley W, Faraone SV, Middleton FA. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):87-95. PMID:23341099 doi:10.1002/ajmg.b.32125
3. ↑ Bailey CG, Ryan RM, Thoeng AD, Ng C, King K, Vanslambrouck JM, Auray-Blais C, Vandenberg RJ, Bröer S, Rasko JE. Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest. 2011 Jan;121(1):446-53. PMID:21123949 doi:10.1172/JCI44474
4. ↑ Abousaab A, Warsi J, Elvira B, Lang F. Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters EAAT1, EAAT2, EAAT3, and EAAT4. J Membr Biol. 2016 Jun;249(3):239-49. doi: 10.1007/s00232-015-9863-0. Epub 2015, Dec 21. PMID:26690923 doi:http://dx.doi.org/10.1007/s00232-015-9863-0
5. ↑ Qiu B, Matthies D, Fortea E, Yu Z, Boudker O. Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport. Sci Adv. 2021 Mar 3;7(10):eabf5814. PMID:33658209 doi:10.1126/sciadv.abf5814
6. ↑ Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci. 1994 Sep;14(9):5559-69. PMID:7521911
7. ↑ Kanai Y, Stelzner M, Nussberger S, Khawaja S, Hebert SC, Smith CP, Hediger MA. The neuronal and epithelial human high affinity glutamate transporter. Insights into structure and mechanism of transport. J Biol Chem. 1994 Aug 12;269(32):20599-606 PMID:7914198
8. ↑ Zerangue N, Kavanaugh MP. Flux coupling in a neuronal glutamate transporter. Nature. 1996 Oct 17;383(6601):634-7. PMID:8857541 doi:10.1038/383634a0