gaba plasma membrane transport proteins

Summary

Summary: A family of plasma membrane neurotransmitter transporter proteins that regulates extracellular levels of the inhibitory neurotransmitter GAMMA-AMINOBUTYRIC ACID. They differ from GABA RECEPTORS, which signal cellular responses to GAMMA-AMINOBUTYRIC ACID. They control GABA reuptake into PRESYNAPTIC TERMINALS in the CENTRAL NERVOUS SYSTEM through high-affinity sodium-dependent transport.

Top Publications

  1. Schousboe A, Madsen K, White H. GABA transport inhibitors and seizure protection: the past and future. Future Med Chem. 2011;3:183-7 pubmed publisher
  2. Sałat K, Więckowska A, Więckowski K, Höfner G, Kamiński J, Wanner K, et al. Synthesis and pharmacological properties of new GABA uptake inhibitors. Pharmacol Rep. 2012;64:817-33 pubmed
    ..Moreover, it did not impair animals' motor coordination in the chimney test. Some of the described pharmacological activities of compound 18 can be partly explained based on its affinity for plasma membrane GABA transporters. ..
  3. Deken S, Wang D, Quick M. Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. J Neurosci. 2003;23:1563-8 pubmed
  4. Matthews E, Rahnama Vaghef A, Eskandari S. Inhibitors of the gamma-aminobutyric acid transporter 1 (GAT1) do not reveal a channel mode of conduction. Neurochem Int. 2009;55:732-40 pubmed publisher
    ..Rather, the results suggest tight coupling of GAT1-mediated charge flux and GABA flux. ..
  5. Mari S, Soragna A, Castagna M, Bossi E, Peres A, Sacchi V. Aspartate 338 contributes to the cationic specificity and to driver-amino acid coupling in the insect cotransporter KAAT1. Cell Mol Life Sci. 2004;61:243-56 pubmed
  6. Sitka I, Allmendinger L, Fülep G, Höfner G, Wanner K. Synthesis of N-substituted acyclic ?-amino acids and their investigation as GABA uptake inhibitors. Eur J Med Chem. 2013;65:487-99 pubmed publisher
    ..34 at GAT1. Unfortunately, the expected GAT3 potency for 2-[tris(4-methoxyphenyl)methoxy]ethyl substituted derivatives was not as high as observed for the respective nipecotic acid derivatives. ..
  7. Fesce R, Giovannardi S, Binda F, Bossi E, Peres A. The relation between charge movement and transport-associated currents in the rat GABA cotransporter rGAT1. J Physiol. 2002;545:739-50 pubmed
    ..The model also predicts the observed voltage dependence of the apparent affinity of the transporter for GABA, and suggests a voltage-independent GABA binding rate with a value around 0.64 microM(-1) s(-1). ..
  8. Frahm C, Haupt C, Weinandy F, Siegel G, Bruehl C, Witte O. Regulation of GABA transporter mRNA and protein after photothrombotic infarct in rat brain. J Comp Neurol. 2004;478:176-88 pubmed
    ..Focal brain ischemia obviously triggers mechanisms that interfere with GAT-1 transcriptional regulation and protein synthesis or turnover. ..
  9. Richerson G, Wu Y. Role of the GABA transporter in epilepsy. Adv Exp Med Biol. 2004;548:76-91 pubmed
    ..Further defining this role may lead to a better understanding of the mechanisms of epilepsy and new avenues for treatment. ..

More Information

Publications62

  1. Cai Y, Cai G, Liu G, Cai Q, Shi J, Shi J, et al. Mice with genetically altered GABA transporter subtype I (GAT1) expression show altered behavioral responses to ethanol. J Neurosci Res. 2006;84:255-67 pubmed
    ..These results demonstrate that GAT1, perhaps in a bi-directional way, modulates some behavioral effects of ethanol. The GAT1 mutant mice provided us a very useful model to investigate the mechanisms of ethanol action in vivo. ..
  2. Liu G, Liu S, Cai G, Sheng Z, Cai Y, Jiang J, et al. Reduced aggression in mice lacking GABA transporter subtype 1. J Neurosci Res. 2007;85:649-55 pubmed
    ..These results showed that GAT1 is an important target involved in the regulation of aggressive behavior in mice, and long-term dysfunction of GAT1 may also result in the alteration of testosterone secretion. ..
  3. Karakossian M, Spencer S, Gomez A, Padilla O, Sacher A, Loo D, et al. Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4). J Membr Biol. 2005;203:65-82 pubmed
    ..Thus, Na+ binding and associated conformational changes constitute the rate-limiting steps in the transport cycle. ..
  4. Liu G, Cai G, Cai Y, Sheng Z, Jiang J, Mei Z, et al. Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1. Neuropsychopharmacology. 2007;32:1531-9 pubmed
    ..These results showed that the absence of GAT1 affects mental status through enhancing the GABAergic system, as well as modifying the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) activity in mice. ..
  5. Clausen R, Madsen K, Larsson O, Frølund B, Krogsgaard Larsen P, Schousboe A. Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol. 2006;54:265-84 pubmed
  6. Imoukhuede P, Moss F, Michael D, Chow R, Lester H. Ezrin mediates tethering of the gamma-aminobutyric acid transporter GAT1 to actin filaments via a C-terminal PDZ-interacting domain. Biophys J. 2009;96:2949-60 pubmed publisher
    ..Our data reveal that actin confines GAT1 to the plasma membrane via ezrin, and this interaction is mediated through the PDZ-interacting domain of GAT1. ..
  7. Meinild A, Loo D, Skovstrup S, Gether U, MacAulay N. Elucidating conformational changes in the gamma-aminobutyric acid transporter-1. J Biol Chem. 2009;284:16226-35 pubmed publisher
  8. Cope D, Di Giovanni G, Fyson S, Orbán G, Errington A, Lorincz M, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392-8 pubmed publisher
    ..These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy. ..
  9. Ueda Y, Doi T, Nagatomo K, Tokumaru J, Takaki M, Willmore L. Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection. Brain Res. 2007;1151:55-61 pubmed
    ..These observations together demonstrated the critical molecular mechanism of the anti-epileptic activity of LEV. ..
  10. Soragna A, Bossi E, Giovannardi S, Pisani R, Peres A. Functionally independent subunits in the oligomeric structure of the GABA cotransporter rGAT1. Cell Mol Life Sci. 2005;62:2877-85 pubmed
    ..We conclude that, although rGAT1 undergoes structural oligomerization, each monomer operates independently. ..
  11. Meinild A, Forster I. Using lithium to probe sequential cation interactions with GAT1. Am J Physiol Cell Physiol. 2012;302:C1661-75 pubmed publisher
    ..Numerical simulations using a nonrapid equilibrium model fully recapitulated our experimental findings. ..
  12. Kanner B. Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J Biol Chem. 2003;278:3705-12 pubmed
    ..Our observations suggest the possibility that the permeation pathway in both modes shares common structural elements. ..
  13. MacAulay N, Zeuthen T, Gether U. Conformational basis for the Li(+)-induced leak current in the rat gamma-aminobutyric acid (GABA) transporter-1. J Physiol. 2002;544:447-58 pubmed
  14. Jasmin L, Wu M, Ohara P. GABA puts a stop to pain. Curr Drug Targets CNS Neurol Disord. 2004;3:487-505 pubmed
  15. Zhu X, Ong W. Changes in GABA transporters in the rat hippocampus after kainate-induced neuronal injury: decrease in GAT-1 and GAT-3 but upregulation of betaine/GABA transporter BGT-1. J Neurosci Res. 2004;77:402-9 pubmed
    ..On the other hand, excessive or prolonged BGT-1 expression might be a factor contributing to astrocytic swelling after brain injury. ..
  16. Wu Y, Wang W, Diez Sampedro A, Richerson G. Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron. 2007;56:851-65 pubmed
    ..We conclude that GAT-1 regulates tonic inhibition by clamping ambient [GABA] at a level high enough to activate high-affinity GABA(A) receptors and that transporter-mediated GABA release can contribute to phasic inhibition. ..
  17. Wu Y, Wang W, Richerson G. Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol. 2003;89:2021-34 pubmed
    ..We propose that fast GABAergic neurotransmission and tonic inhibition can be independently modified and play complementary roles in control of neuronal excitability. ..
  18. Cherubino F, Miszner A, Renna M, Sangaletti R, Giovannardi S, Bossi E. GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction. Cell Mol Life Sci. 2009;66:3797-808 pubmed publisher
    ..This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data. ..
  19. Grossman T, Nelson N. Effect of sodium lithium and proton concentrations on the electrophysiological properties of the four mouse GABA transporters expressed in Xenopus oocytes. Neurochem Int. 2003;43:431-43 pubmed
    ..Conversely, addition of GABA to GAT3 expressing oocytes, in the presence of 80 mM Li(+), inhibited the leak currents. ..
  20. McHugh E, Zhu W, Milgram S, Mager S. The GABA transporter GAT1 and the MAGUK protein Pals1: interaction, uptake modulation, and coexpression in the brain. Mol Cell Neurosci. 2004;26:406-17 pubmed
    ..We hypothesize that Pals1 contributes to the stability of the GAT1, thus promoting the expression level of the transporter protein. In the CNS, Pals1 may stabilize GAT1 at appropriate levels in specific GABAergic neurons. ..
  21. Clausen R, Frølund B, Larsson O, Schousboe A, Krogsgaard Larsen P, White H. A novel selective gamma-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS. Neurochem Int. 2006;48:637-42 pubmed
    ..An overview of the development and characterisation of EF1502 is presented here. ..
  22. Zomot E, Zhou Y, Kanner B. Proximity of transmembrane domains 1 and 3 of the gamma-aminobutyric acid transporter GAT-1 inferred from paired cysteine mutagenesis. J Biol Chem. 2005;280:25512-6 pubmed
    ..The inhibition by cadmium was only observed when the cysteine pairs were introduced in the same polypeptide. Our results suggest that transmembrane domains 1 and 3 come in close proximity within the transporter monomer. ..
  23. Korkhov V, Farhan H, Freissmuth M, Sitte H. Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II. J Biol Chem. 2004;279:55728-36 pubmed
  24. Pow D, Sullivan R, Williams S, Scott H, Dodd P, Finkelstein D. Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans. Cell Tissue Res. 2005;320:379-92 pubmed
    ..We suggest that differences in GAT distribution, especially the expression of GAT-3 by oligodendrocytes in humans, must be accommodated in extrapolating rodent models of GABA homeostasis to humans. ..
  25. Kanner B. Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol. 2006;213:89-100 pubmed
    ..In this review the functional results on prototypes of the two families, the GABA transporter GAT-1 and the glutamate transporters GLT-1 and EAAC1, are described and discussed within the perspective provided by the novel structures. ..
  26. Bicho A, Grewer C. Rapid substrate-induced charge movements of the GABA transporter GAT1. Biophys J. 2005;89:211-31 pubmed
    ..Based on the results, a new alternating access sequential-binding model is proposed for GAT1's transport cycle that describes the results presented here and those by others. ..
  27. Zhou Y, Bennett E, Kanner B. The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands. J Biol Chem. 2004;279:13800-8 pubmed
    ..2003) J. Biol. Chem. 278, 37052-37063), suggest that the extracellular part of TMD I is conformationally sensitive, lines the permeation pathway, and forms a more extended structure than expected from a membrane-embedded alpha-helix. ..
  28. Dvorzhak A, Myakhar O, Unichenko P, Kirmse K, Kirischuk S. Estimation of ambient GABA levels in layer I of the mouse neonatal cortex in brain slices. J Physiol. 2010;588:2351-60 pubmed publisher
  29. Rosenberg A, Kanner B. The substrates of the gamma-aminobutyric acid transporter GAT-1 induce structural rearrangements around the interface of transmembrane domains 1 and 6. J Biol Chem. 2008;283:14376-83 pubmed publisher
    ..Thus, the degree of inhibition by CuPh is not a simple function of the accessibility of the individual cysteines but also involves structural rearrangements around the TM 1b/TM 6a interface. ..
  30. Jin X, Pare J, Smith Y. Differential localization and function of GABA transporters, GAT-1 and GAT-3, in the rat globus pallidus. Eur J Neurosci. 2011;33:1504-18 pubmed publisher
    ..In conclusion, these data indicate that GAT-1 and GAT-3 represent different target sites through which GABA reuptake may subserve complementary regulation of GABAergic transmission in the rat GP. ..
  31. Bragina L, Marchionni I, Omrani A, Cozzi A, Pellegrini Giampietro D, Cherubini E, et al. GAT-1 regulates both tonic and phasic GABA(A) receptor-mediated inhibition in the cerebral cortex. J Neurochem. 2008;105:1781-93 pubmed publisher
  32. Allen N, Rossi D, Attwell D. Sequential release of GABA by exocytosis and reversed uptake leads to neuronal swelling in simulated ischemia of hippocampal slices. J Neurosci. 2004;24:3837-49 pubmed
    ..These data show that ischemia releases GABA initially by exocytosis and then by reversal of GAT-1 transporters and that the resulting Cl- influx through GABA(A) receptor channels causes potentially neurotoxic cell swelling. ..
  33. Farhan H, Reiterer V, Korkhov V, Schmid J, Freissmuth M, Sitte H. Concentrative export from the endoplasmic reticulum of the gamma-aminobutyric acid transporter 1 requires binding to SEC24D. J Biol Chem. 2007;282:7679-89 pubmed
  34. Medina Ceja L, Sandoval García F, Pardo Peña K. Effect of early glutamate exposure on EAAT-3 and GAT-1 protein expression in cells of the dentate gyrus and CA1 region of the adult rat hippocampus. Arch Med Res. 2011;42:433-8 pubmed publisher
  35. Kinney G, Spain W. Synaptically evoked GABA transporter currents in neocortical glia. J Neurophysiol. 2002;88:2899-908 pubmed
  36. Wu Y, Wang W, Richerson G. The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters. J Neurophysiol. 2006;96:2425-36 pubmed
    ..The source of GABA release may be conceptually less important in determining the amount of tonic inhibition than the factors that control the equilibrium of GABA transporters. ..
  37. Doi T, Ueda Y, Tokumaru J, Willmore L. Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe(+++)-induced epileptic rats. Brain Res Mol Brain Res. 2005;142:91-6 pubmed
    ..In addition to allosteric activation of GABA(A) receptors, this study suggests that CLB might exhibit its antiepileptic action by increasing GLT-1 expression and GAT3 in the hippocampus of rats with chronic seizures. ..
  38. Kinney G. GAT-3 transporters regulate inhibition in the neocortex. J Neurophysiol. 2005;94:4533-7 pubmed
  39. Wang D, Quick M. Trafficking of the plasma membrane gamma-aminobutyric acid transporter GAT1. Size and rates of an acutely recycling pool. J Biol Chem. 2005;280:18703-9 pubmed
    ..This insertion could represent the fusion of one transporter-containing vesicle. ..
  40. Schousboe A. Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem Res. 2003;28:347-52 pubmed
  41. Clarkson A, Huang B, Macisaac S, Mody I, Carmichael S. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305-9 pubmed publisher
    ..Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries. ..
  42. Overstreet L, Westbrook G. Synapse density regulates independence at unitary inhibitory synapses. J Neurosci. 2003;23:2618-26 pubmed
    ..Thus, interplay between release site density and transporter action determines the independence of unitary inhibitory synapses. ..
  43. MacAulay N, Meinild A, Zeuthen T, Gether U. Residues in the extracellular loop 4 are critical for maintaining the conformational equilibrium of the gamma-aminobutyric acid transporter-1. J Biol Chem. 2003;278:28771-7 pubmed
  44. Ben Yona A, Kanner B. Transmembrane domain 8 of the {gamma}-aminobutyric acid transporter GAT-1 lines a cytoplasmic accessibility pathway into its binding pocket. J Biol Chem. 2009;284:9727-32 pubmed publisher
  45. Sapin E, Lapray D, Berod A, Goutagny R, Leger L, Ravassard P, et al. Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS ONE. 2009;4:e4272 pubmed publisher
    ..From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles...
  46. Gonzalez Burgos G, Rotaru D, Zaitsev A, Povysheva N, Lewis D. GABA transporter GAT1 prevents spillover at proximal and distal GABA synapses onto primate prefrontal cortex neurons. J Neurophysiol. 2009;101:533-47 pubmed publisher
  47. Farhan H, Reiterer V, Kriz A, Hauri H, Pavelka M, Sitte H, et al. Signal-dependent export of GABA transporter 1 from the ER-Golgi intermediate compartment is specified by a C-terminal motif. J Cell Sci. 2008;121:753-61 pubmed publisher
    ..To the best of our knowledge, the VMI-motif of GAT1 provides the first example of a cargo-based motif that specifies export from the ERGIC. ..
  48. Holton K, Loder M, Melikian H. Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization. Nat Neurosci. 2005;8:881-8 pubmed
    ..The DAT endocytic signal does not conform to classic internalization motifs, suggesting that SLC6 neurotransmitter transporters may have evolved unique endocytic mechanisms. ..
  49. Melamed N, Kanner B. Transmembrane domains I and II of the gamma-aminobutyric acid transporter GAT-4 contain molecular determinants of substrate specificity. Mol Pharmacol. 2004;65:1452-61 pubmed
    ..The size of the side chain at positions 61 and 94 seems to determine the ability of substrate and substrate analogs to interact with the transporter. ..
  50. Hoogland G, Spierenburg H, van Veelen C, van Rijen P, van Huffelen A, de Graan P. Synaptosomal glutamate and GABA transport in patients with temporal lobe epilepsy. J Neurosci Res. 2004;76:881-90 pubmed
    ..Our findings provide evidence for impaired function of glutamate and GABA transporters in human TLE. ..
  51. Sipilä S, Huttu K, Voipio J, Kaila K. GABA uptake via GABA transporter-1 modulates GABAergic transmission in the immature hippocampus. J Neurosci. 2004;24:5877-80 pubmed
    ..Our results indicate a novel role for GAT-1 in the control of endogenous activity of the immature hippocampus. ..
  52. Héja L, Karacs K, Kardos J. Role for GABA and Glu plasma membrane transporters in the interplay of inhibitory and excitatory neurotransmission. Curr Top Med Chem. 2006;6:989-95 pubmed
  53. Madsen K, White H, Schousboe A. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther. 2010;125:394-401 pubmed publisher