Biology:GABA transporter type 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1][2][3] It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.[4][5]

Structure

GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.[6][4]

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).[7][8] 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.[9] The presence of a Cl−/Cl− exchange is also proposed because the Cl− transported across the membrane does not affect the net charge.[10] GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.[11] The GABA affinity (Km) of the mouse isoform of GAT1 is 8 μM.[12]

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.[13][6] 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.[6]

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.[6]
  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.[6]
  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.[6]

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.[14][15] 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..[13]

Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's and stroke.[16]

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.[17]

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.[18]

Interactions

SLC6A1 has been shown to interact with STX1A.[19][20][21]

See also

References

  1. ↑ "Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25". Genomics 29 (1): 302–304. September 1995. doi:10.1006/geno.1995.1253. PMID 8530094. 
  2. ↑ "Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6529. 
  3. ↑ "Structure, function, and plasticity of GABA transporters". Frontiers in Cellular Neuroscience 8: 161. 2014. doi:10.3389/fncel.2014.00161. PMID 24987330. 
  4. ↑ 4.0 4.1 "GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?". GABABReceptor Pharmacology - A Tribute to Norman Bowery. Advances in Pharmacology. 58. 2010. pp. 175–204. doi:10.1016/S1054-3589(10)58008-6. ISBN 9780123786470. 
  5. ↑ "Defining the phenotypic spectrum of SLC6A1 mutations". Epilepsia 59 (2): 389–402. February 2018. doi:10.1111/epi.13986. PMID 29315614. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective". Frontiers in Chemistry 6: 397. 2018. doi:10.3389/fchem.2018.00397. PMID 30255012. Bibcode: 2018FrCh....6..397Z. 
  7. ↑ "Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity". Pharmacogenetics and Genomics 19 (1): 53–65. January 2009. doi:10.1097/FPC.0b013e328318b21a. PMID 19077666. 
  8. ↑ "The subcellular localization of GABA transporters and its implication for seizure management". Neurochemical Research 40 (2): 410–419. February 2015. doi:10.1007/s11064-014-1494-9. PMID 25519681. 
  9. ↑ "Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia". Frontiers in Systems Neuroscience 5: 63. 28 July 2011. doi:10.3389/fnsys.2011.00063. PMID 21847373. 
  10. ↑ "Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1" (in English). The Journal of Biological Chemistry 275 (48): 37414–37422. December 2000. doi:10.1074/jbc.M007241200. PMID 10973981. 
  11. ↑ "GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications". Brain Research. Brain Research Reviews 45 (3): 196–212. July 2004. doi:10.1016/j.brainresrev.2004.03.003. PMID 15210304. 
  12. ↑ "GABA and Glutamate Transporters in Brain". Frontiers in Endocrinology 4: 165. 2013. doi:10.3389/fendo.2013.00165. PMID 24273530. 
  13. ↑ 13.0 13.1 "GABA Receptor". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK526124/. Retrieved 2022-04-11. 
  14. ↑ "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. February 2001. doi:10.1176/appi.ajp.158.2.256. PMID 11156808. 
  15. ↑ "[Schizophrenia and cortical GABA neurotransmission]". Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica 112 (5): 439–452. 2010. PMID 20560363. 
  16. ↑ "Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function". Neuropharmacology. Neurotransmitter Transporters 161: 107644. December 2019. doi:10.1016/j.neuropharm.2019.05.021. PMID 31108110. 
  17. ↑ "Enhanced tonic GABAA inhibition in typical absence epilepsy". Nature Medicine 15 (12): 1392–1398. December 2009. doi:10.1038/nm.2058. PMID 19966779. 
  18. ↑ "GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses". Hypertension Research 43 (10): 995–1005. October 2020. doi:10.1038/s41440-020-0470-9. PMID 32451494. 
  19. ↑ "Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A". The Journal of Neuroscience 18 (16): 6103–6112. August 1998. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMID 9698305. 
  20. ↑ "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. April 2002. doi:10.1073/pnas.082712899. PMID 11960023. Bibcode: 2002PNAS...99.5686Q. 
  21. ↑ "Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A". Nature Neuroscience 3 (10): 998–1003. October 2000. doi:10.1038/79939. PMID 11017172. 

Further reading

  • "Cloning of the human brain GABA transporter". FEBS Letters 269 (1): 181–184. August 1990. doi:10.1016/0014-5793(90)81149-I. PMID 2387399. 
  • "The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain". The Journal of Biological Chemistry 272 (2): 1203–1210. January 1997. doi:10.1074/jbc.272.2.1203. PMID 8995422. 
  • "Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition". The Journal of Biological Chemistry 272 (26): 16096–16102. June 1997. doi:10.1074/jbc.272.26.16096. PMID 9195904. 
  • "Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex". NeuroReport 9 (3): 467–470. February 1998. doi:10.1097/00001756-199802160-00020. PMID 9512391. 
  • "Neuronal and glial localization of GAT-1, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex". The Journal of Comparative Neurology 396 (1): 51–63. June 1998. doi:10.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>3.0.CO;2-H. PMID 9623887. 
  • "Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus". Neuroscience 88 (2): 521–534. January 1999. doi:10.1016/S0306-4522(98)00226-7. PMID 10197772. 
  • "A light and electron microscopic study of GAT-1-positive cells in the cerebral cortex of man and monkey". Journal of Neurocytology 27 (10): 719–730. October 1998. doi:10.1023/A:1006946717065. PMID 10640187. 
  • "Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation". The Journal of Biological Chemistry 276 (46): 42932–42937. November 2001. doi:10.1074/jbc.M107638200. PMID 11555659. 
  • "Development of GABAergic neurons and their transporter in human temporal cortex". Pediatric Neurology 25 (5): 390–396. November 2001. doi:10.1016/S0887-8994(01)00348-4. PMID 11744314. 
  • "Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes". The Journal of Biological Chemistry 278 (6): 3705–3712. February 2003. doi:10.1074/jbc.M210525200. PMID 12446715. 
  • "The interaction of the gamma-aminobutyric acid transporter GAT-1 with the neurotransmitter is selectively impaired by sulfhydryl modification of a conformationally sensitive cysteine residue engineered into extracellular loop IV". The Journal of Biological Chemistry 278 (44): 42950–42958. October 2003. doi:10.1074/jbc.M209307200. PMID 12925537. 
  • "The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands". The Journal of Biological Chemistry 279 (14): 13800–13808. April 2004. doi:10.1074/jbc.M311579200. PMID 14744863. 
  • "Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1)". NeuroReport 15 (1): 9–12. January 2004. doi:10.1097/00001756-200401190-00003. PMID 15106822. 
  • "Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II". The Journal of Biological Chemistry 279 (53): 55728–55736. December 2004. doi:10.1074/jbc.M409449200. PMID 15496410. 

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



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