GABA transporter type 1

GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1 gene and belongs to the solute carrier 6 (SLC6) family of transporters.[5][6][7] It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.[8][9]

SLC6A1
Identifiers
AliasesSLC6A1, GABATHG, GABATR, GAT1, MAE, GABA transporter 1, solute carrier family 6 member 1
External IDsOMIM: 137165 MGI: 95627 HomoloGene: 2290 GeneCards: SLC6A1
Orthologs
SpeciesHumanMouse
Entrez

6529

232333

Ensembl

ENSG00000157103

ENSMUSG00000030310

UniProt

P30531

P31648

RefSeq (mRNA)

NM_003042
NM_001348250
NM_001348251
NM_001348252
NM_001348253

NM_178703

RefSeq (protein)

NP_003033
NP_001335179
NP_001335180
NP_001335181
NP_001335182

NP_848818

Location (UCSC)Chr 3: 10.99 – 11.04 MbChr 6: 114.26 – 114.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.[10][8]

Function

GAT1 is a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft by shuttling it to presynaptic neurons (where GABA can be recycled) and astrocytes (where GABA can be broken down).[11][12] GABA Transporter 1 uses energy from the dissipation of a Na+ gradient, aided by the presence of a Cl− gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na+: 1 Cl−: 1 GABA.[13] The presence of a Cl−/Cl− exchange is also proposed because the Cl− transported across the membrane does not affect the net charge.[14] GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.[15] The GABA affinity (Km) of the mouse isoform of GAT1 is 8 μM.[16]

In the brain of a mature mammal, glutamate is converted to GABA by the enzyme glutamate decarboxylase (GAD) along with the addition of vitamin B6. GABA is then packed and released into the post-synaptic terminals of neurons after synthesis. GABA can also be used to form succinate, which is involved in the citric acid cycle.[17][10] Vesicle uptake has been shown to prioritize newly synthesized GABA over preformed GABA, though the reasoning behind this mechanism is currently not completely understood.

The regulation of the modular functioning of GATs is highly dependent on a multitude of second messengers and synaptic proteins.[10]

Translocation cycle

Throughout the translocation cycle, GAT1 assumes three different conformations:

  1. Open-to-out. In this conformation, 2 extracellular Na+ ions are co-transported into the neuron along with 1 GABA and 1 Cl− that bind to the empty transporter, thus making it fully loaded. In prokaryotes, it has been found that transport does not require Cl−. In mammals, the Cl− ion is required to offset the positive charge of the Na+ in order to maintain the proper membrane potential.[10]
  2. Occluded-out. Once fully loaded, this conformation prevents the release of ions/substrate into the cytoplasm or the extracellular space/synapse. The Na+, Cl−, and GABA are bound to the transporter until it changes conformation.[10]
  3. Open-to-in. The transporter, which was previously facing the synapse, becomes inward facing and can now release the ions and GABA into the neuron's cytoplasm. Once empty, the transporter occludes its binding site and flips to become outward facing so a new translocation cycle can begin.[10]

Clinical significance

Research has shown that schizophrenia patients have GABA synthesis and expression altered, leading to the conclusion that GABA Transporter-1, which adds and removes GABA from the synaptic cleft, plays a role in the development of neurological disorders such as schizophrenia.[18][19] GABA and its precursor glutamate have opposite functions within the nervous system. Glutamate is considered an excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. Glutamate and GABA imbalances contribute to different neurological pathologies..[17]

Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's and stroke.[20]

A study on genetic absence epilepsy rats from Strasbourg (GAERS) found that poor GABA uptake by GAT1 caused an increase in tonic current of GABAA. In the two most understood forms of absence epilepsy, synaptic GABAA receptors including GAT1 play a major role in seizure development. Blocking GAT1 in non-epileptic control (NEC) rats caused tonic current to increase to a rate similar to that of GAERS of the same age. This common cellular control site shows a possible target for future seizure treatments.[21]

Glutamate and GABA have also been found to interact within the nucleus tractus solitarii (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) of the brain to modulate blood pressure.[22]

Interactions

SLC6A1 has been shown to interact with STX1A.[23][24][25]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000157103 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000030310 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Huang F, Shi LJ, Heng HH, Fei J, Guo LH (September 1995). "Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25". Genomics. 29 (1): 302–304. doi:10.1006/geno.1995.1253. PMID 8530094.
  6. "Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1".
  7. Scimemi A (2014). "Structure, function, and plasticity of GABA transporters". Frontiers in Cellular Neuroscience. 8: 161. doi:10.3389/fncel.2014.00161. PMC 4060055. PMID 24987330.
  8. Gonzalez-Burgos G (2010). "GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?". GABABReceptor Pharmacology - A Tribute to Norman Bowery. Advances in Pharmacology. Vol. 58. pp. 175–204. doi:10.1016/S1054-3589(10)58008-6. ISBN 9780123786470. PMID 20655483.
  9. Johannesen KM, Gardella E, Linnankivi T, Courage C, de Saint Martin A, Lehesjoki AE, et al. (February 2018). "Defining the phenotypic spectrum of SLC6A1 mutations". Epilepsia. 59 (2): 389–402. doi:10.1111/epi.13986. PMC 5912688. PMID 29315614.
  10. Zafar S, Jabeen I (2018). "Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective". Frontiers in Chemistry. 6: 397. Bibcode:2018FrCh....6..397Z. doi:10.3389/fchem.2018.00397. PMC 6141625. PMID 30255012.
  11. Hirunsatit R, George ED, Lipska BK, Elwafi HM, Sander L, Yrigollen CM, et al. (January 2009). "Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity". Pharmacogenetics and Genomics. 19 (1): 53–65. doi:10.1097/FPC.0b013e328318b21a. PMC 2791799. PMID 19077666.
  12. Madsen KK, Hansen GH, Danielsen EM, Schousboe A (February 2015). "The subcellular localization of GABA transporters and its implication for seizure management". Neurochemical Research. 40 (2): 410–419. doi:10.1007/s11064-014-1494-9. PMID 25519681. S2CID 19008879.
  13. Jin XT, Galvan A, Wichmann T, Smith Y (28 July 2011). "Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia". Frontiers in Systems Neuroscience. 5: 63. doi:10.3389/fnsys.2011.00063. PMC 3148782. PMID 21847373.
  14. Loo DD, Eskandari S, Boorer KJ, Sarkar HK, Wright EM (December 2000). "Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1". The Journal of Biological Chemistry. 275 (48): 37414–37422. doi:10.1074/jbc.M007241200. PMID 10973981.
  15. Conti F, Minelli A, Melone M (July 2004). "GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications". Brain Research. Brain Research Reviews. 45 (3): 196–212. doi:10.1016/j.brainresrev.2004.03.003. PMID 15210304. S2CID 19003675.
  16. Zhou Y, Danbolt NC (2013). "GABA and Glutamate Transporters in Brain". Frontiers in Endocrinology. 4: 165. doi:10.3389/fendo.2013.00165. PMC 3822327. PMID 24273530.
  17. Allen MJ, Sabir S, Sharma S (2022). "GABA Receptor". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252380. Retrieved 2022-04-11.
  18. Volk D, Austin M, Pierri J, Sampson A, Lewis D (February 2001). "GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons". The American Journal of Psychiatry. 158 (2): 256–265. doi:10.1176/appi.ajp.158.2.256. PMID 11156808.
  19. Hashimoto T, Matsubara T, Lewis DA (2010). "[Schizophrenia and cortical GABA neurotransmission]". Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica. 112 (5): 439–452. PMID 20560363.
  20. Kickinger S, Hellsberg E, Frølund B, Schousboe A, Ecker GF, Wellendorph P (December 2019). "Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function". Neuropharmacology. Neurotransmitter Transporters. 161: 107644. doi:10.1016/j.neuropharm.2019.05.021. PMID 31108110. S2CID 156055973.
  21. Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, et al. (December 2009). "Enhanced tonic GABAA inhibition in typical absence epilepsy". Nature Medicine. 15 (12): 1392–1398. doi:10.1038/nm.2058. PMC 2824149. PMID 19966779.
  22. Dupont AG, Légat L (October 2020). "GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses". Hypertension Research. 43 (10): 995–1005. doi:10.1038/s41440-020-0470-9. PMID 32451494. S2CID 218864718.
  23. Beckman ML, Bernstein EM, Quick MW (August 1998). "Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A". The Journal of Neuroscience. 18 (16): 6103–6112. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMC 6793212. PMID 9698305.
  24. Quick MW (April 2002). "Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner". Proceedings of the National Academy of Sciences of the United States of America. 99 (8): 5686–5691. Bibcode:2002PNAS...99.5686Q. doi:10.1073/pnas.082712899. PMC 122832. PMID 11960023.
  25. Deken SL, Beckman ML, Boos L, Quick MW (October 2000). "Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A". Nature Neuroscience. 3 (10): 998–1003. doi:10.1038/79939. PMID 11017172. S2CID 11312913.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.