Excitatory amino acid transporter 5 (EAAT5) is a protein that is known to be alternately spliced and to be abundantly expressed in the retina by populations of neurons including photoreceptors and bipolar cells. EAAT5 acts as a slow glutamate transporter and also as glutamate-gated chloride channel, the chloride conductance being large enough for EAAT5 to serve functionally as an "inhibitory" glutamate receptor. However, there has been a long-standing view that the classically spliced form of EAAT5 is not abundant or widespread in the brain and so it has not been extensively investigated in the literature. We recently identified a human-specific splicing form of EAAT5 that was not expressed by rodents but was shown to be a functional glutamate transporter. We have examined the expression of this form of EAAT5, hEAAT5v at the mRNA, and protein level in human brain, and show that populations of human cortical pyramidal neurons and cerebellar Purkinje cells show significant expression of hEAAT5v. Accordingly, we infer that EAAT5 may well be a player in modulating neuronal function in the human brain and propose that its localization in both glutamatergic and GABAergic neurons could be compatible with a role in influencing intracellular chloride and thereby neuronal parameters such as membrane potential rather than acting as a presynaptic glutamate transporter.

Discipline of Anatomy and Histology School of Medical Sciences and Bosch Institute Sydney Medical School The University of Sydney Sydney New South Wales Australia

Laboratory of Neurobiology and Pathological Physiology Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Brno Czech Republic

UQ Centre for Clinical Research The University of Queensland Brisbane Queensland Australia

Zobrazit více v PubMed

Arriza, J. L., Eliasof, S., Kavanaugh, M. P., & Amara, S. G. (1997). Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proceedings of the National Academy of Sciences of the United States of America, 94, 4155-4160.

BioGPS. (2019). http://biogps.org/#goto=genereport&id=6512

Dalet, A., Bonsacquet, J., Gaboyard-Niay, S., Calin-Jageman, I., Chidavaenzi, R. L., Venteo, S., … Chabbert, C. (2001). Glutamate transporters EAAT4 and EAAT5 are expressed in vestibular hair cells calyx endings. PLoS One, 7(9), e46261.

Danbolt, N. C. (2001). Glutamate uptake. Progress in Neurobiology, 65, 1-105.

Gameiro, A., Braams, S., Rauen, T., & Grewer, C. (2011). The discovery of slowness: Low-capacity transport and slow anion channel gating by the glutamate transporter EAAT5. Biophysical Journal, 100, 2623-2632.

GeneCards. (2019). https://genecards.weizmann.ac.il/v3/cgi-bin/carddisp.pl?gene=SLC1A7.

Geseman, M., Lesslauer, A., Maurer, C. M., Schönthaler, H. B., & Neuhauss, S. C. F. (2010). Phylogenetic analysis of the vertebrate excitatory/neutral amino acid transporter (SLC1/EAAT) family reveals lineages specific subfamilies. BMC Evolutionary Biology, 10, 117 http://www. biomedcentral.com/1471-2148/10/117

Jiang, J., & Amara, S. G. (2011). New views of glutamate transporter structure and function: Advances and challenges. Neuropharmacology, 60, 172-181.

Lee, A., Anderson, A. R., Barnett, N. L., Chan, A., & Pow, D. V. (2011). Expression of multiple glutamate transporter splice variants in the rodent testis. Asian Journal of Andrology, 13, 254-265.

Lee, A., Anderson, A. R., Barnett, N. L., Stevens, M. G., & Pow, D. V. (2012). Alternate splicing and expression of the glutamate transporter EAAT5 in the rat retina. Gene, 506, 283-288.

Lee, A., Anderson, A. R., Beasley, S. J., Barnett, N. L., Poronnik, P., & Pow, D. V. (2012). A new splice variant of the glutamate-aspartate transporter: Cloning and immunolocalization of GLAST1c in rat, pig and human brains. Journal of Chemical Neuroanatomy, 43, 64-75.

Lee, A., Anderson, A. R., Stevens, M., Beasley, S., Barnett, N. L., & Pow, D. V. (2013). Excitatory amino acid transporter 5 is widely expressed in peripheral tissues. European Journal of Histochemistry, 57(1), e11.

Lee, A., Anderson, A. R., Stevens, M. G., & Pow, D. V. (2011). Exon 4-skipping GLT-1: A new form of an abundantly expressed glutamate transporter. Neuroscience Letters, 504, 228-231.

Lee, A., & Pow, D. V. (2010). Astrocytes: Glutamate transport and alternate splicing of transporters. The International Journal of Biochemistry & Cell Biology, 42, 1901-1906.

Lee, A., Stevens, M. G., Anderson, A. R., Kwan, A., Balcar, V. J., & Pow, D. V. (2016). A novel splice variant of the excitatory amino acid transporter 5: Cloning, immunolocalization and functional characterization of hEAAT5v in human retina. Neurochemistry International, S0197-0186(16), 30404-30401.

Lin, C. L., Bristol, L. A., Jin, L., Dykes-Hoberg, M., Crawford, T., Clawson, L., & Rothstein, J. D. (1998). Aberrant RNA processing in a neurodegenerative disease: The cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron, 20, 589-602.

Meyer, T., Fromm, A., Münch, C., Schwalenstöcker, B., Fray, A. E., Ince, P. G., … Shaw, P. J. (1999). The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. Journal of the Neurological Sciences, 170, 45-50.

Ochiai, H., Saito, M., Maruo, T., & Kanemaki, N. (2010). Molecular cloning of canine excitatory amino acid transporter 5 and its detection in primary lens epithelial cells. Experimental Animals, 59(4), 449-457.

Pow, D. V. (1993). Immunocytochemistry of amino-acids in the rodent pituitary using extremely specific, very high-titer antisera. Journal of Neuroendocrinology, 5, 349-356.

Pow, D. V., & Barnett, N. L. (2000). Developmental expression of excitatory amino acid transporter 5: A photoreceptor and bipolar cell glutamate transporter in rat retina. Neuroscience Letters, 280, 21-24.

Pow, D. V., Sullivan, R., & Scott, H. (2003). Antibody production and immunocytochemical localization of amino acid transporters. Methods in Molecular Biology, 227, 213-244.

Pow, D. V., Sullivan, R., Williams, S., & WoldeMussie, E. (2005). Transporters and oxidative stress. In Macular degeneration (pp. 123-148). Berlin, Germany: Springer-Verlag.

Rauen, T., Wiessner, M., Sullivan, R., Lee, A., & Pow, D. V. (2004). A new GLT1 splice variant: Cloning and immunolocalization of GLT1c in the mammalian retina and brain. Neurochemistry International, 45, 1095e1106.

Reye, P., Sullivan, R., & Pow, D. V. (2002). Distribution of two splice variants of the glutamate transporter GLT-1 in the developing rat retina. The Journal of Comparative Neurology, 447, 323-330.

Reye, P., Sullivan, R., Scott, H., & Pow, D. V. (2002). Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary. Glia, 38(3), 246-255.

Ryan, R. M., & Vandenberg, R. J. (2005). A channel in a transporter. Clinical and Experimental Pharmacology & Physiology, 32, 1-6.

Schneider, N., Cordeiro, S., Machtens, J. P., Braams, S., Rauen, T., & Fahlke, C. (2014). Functional properties of the retinal glutamate transporters GLT-1c and EAAT5. The Journal of Biological Chemistry, 289, 1815-1824.

Šerý, O., Sultana, N., Kashem, M. A., Pow, D. V., & Balcar, V. J. (2015). GLAST but not least - Distribution, function, genetics and epigenetics of L-glutamate transport in brain - Focus on GLAST/EAAT1. Neurochemical Research, 40, 2461-2471.

Sheldon, A. L., & Robinson, M. B. (2007). The role of glutamate transporters in neurodegenerative disease and potential opportunities for intervention. Neurochemistry International, 51, 333-355.

Sullivan, R., Rauen, T., Fischer, F., Wiessner, M., Grewer, C., Bicho, A., & Pow, D. V. (2004). Cloning, transport properties, and differential localization of two splice variants of GLT-1 in the rat CNS: Implications for CNS glutamate homeostasis. Glia, 45(2), 155-169.

Susarla, B. T., Seal, R. P., Zelenaia, O., Watson, D. J., Wolfe, J. H., Amara, S. G., & Robinson, M. B. (2004). Differential regulation of GLAST immunoreactivity and activity by protein kinase C: Evidence for modification of amino and carboxyl termini. Journal of Neurochemistry, 91(5), 1151-1163.

Wersinger, E1., Schwab, Y., Sahel, J. A., Rendon, A., Pow, D. V., Picaud, S., & Roux, M. J. (2006). The glutamate transporter EAAT5 works as a presynaptic receptor in mouse rod bipolar cells. The Journal of Physiology, 577, 221-234.

Zhou, Y., & Danbolt, N. C. (2013). GABA and glutamate transporters in brain. Frontiers in Endocrinology, 4, 165.

Aspartate in the Brain: A Review