GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1gene 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]
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:
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]
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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID8530094.
^ abGonzalez-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. ISBN9780123786470. PMID20655483.
^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. PMID25519681. S2CID19008879.
^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. PMID15210304. S2CID19003675.
^ abAllen MJ, Sabir S, Sharma S (2022). "GABA Receptor". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30252380. Retrieved 2022-04-11.
^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. PMID11156808.
^Hashimoto T, Matsubara T, Lewis DA (2010). "[Schizophrenia and cortical GABA neurotransmission]". Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica. 112 (5): 439–452. PMID20560363.
^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. PMID31108110. S2CID156055973.
Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A (June 1998). "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. doi:10.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>3.0.CO;2-H. PMID9623887. S2CID33438310.
Augood SJ, Waldvogel HJ, Münkle MC, Faull RL, Emson PC (January 1999). "Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus". Neuroscience. 88 (2): 521–534. doi:10.1016/S0306-4522(98)00226-7. PMID10197772. S2CID2514970.
Ong WY, Yeo TT, Balcar VJ, Garey LJ (October 1998). "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. doi:10.1023/A:1006946717065. PMID10640187. S2CID39552099.
Hachiya Y, Takashima S (November 2001). "Development of GABAergic neurons and their transporter in human temporal cortex". Pediatric Neurology. 25 (5): 390–396. doi:10.1016/S0887-8994(01)00348-4. PMID11744314.
