Abstract
The GABA transporter plays a well-established role in reuptake of GABA after synaptic release. The anticonvulsant effect of tiagabine appears to result largely from blocking this reuptake. However, there is another side to the GABA transporter, contributing to GABA release by reversing in response to depolarization. We have recently shown that this form of GABA release is induced by even small increases in extracellular [K+], and has a powerful inhibitory effect on surrounding neurons. This transporter-mediated GABA release is enhanced by the anticonvulsants gabapentin and vigabatrin. The latter drug also potently increases ambient [GABA], inducing tonic inhibition of neurons. Here we review the evidence in support of a physiological role for GABA transporter reversal, and the evidence that it is increased by high-frequency firing. We postulate that the GABA transporter is a major determinant of the level of tonic inhibition, and an important source of GABA release during seizures. These recent findings indicate that the GABA transporter plays a much more dynamic role in control of brain excitability than has previously been recognized. Further defining this role may lead to a better understanding of the mechanisms of epilepsy and new avenues for treatment.
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Attwell D, Barbour B, Szatkowski M. Nonvesicular release of neurotransmitter. Neuron 1993; 11: 401–407.
Belhage B, Hansen GH, Schousboe A. Depolarization by K* and glutamate activates different neurotransmitter release mechanisms in GABAergic neurons: vesicular versus nonvesicular release of GABA. Neurosci 1993; 54: 1019–1034.
Bernath S, Zigmond MJ. Characterization of [3H]GABA release from striatal slices: evidence for a calcium-independent process via the GABA uptake system. Neuroscience 1988; 27: 563–570.
Bernstein EM, Quick MW. Regulation of y-aminobutyric acid (GABA) transporters by extracellular GABA. J Biol Chem 1999; 274: 889–895.
Borden LA. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 1996; 29: 335–356.
Brickley SG, Cull-Candy SG, Farrant M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J Physiol Lond 1996; 497: 753–759.
Cammack JN, Rakhilin SV, Schwartz EA. A GABA transporter operates asymmetrically and with variable stoichiometry. Neuron 1994; 13: 949–960.
Cammack JN, Schwartz EA. Ions required for the electrogenic transport of GABA by horizontal cells of the catfish. J Physiol Lond 1993; 472: 81–102.
Cherubini E, Gaiarsa JL, Ben-Ari Y. GABA: An excitatory transmitter in early postnatal life. Trends Neurosci 1991; 14: 515–519.
Clark JA, Amara SG. Stable expression of a neuronal gamma-aminobutyric acid transporter, GAT-3, in mammalian cells demonstrates unique pharmacological properties and ion dependence. Mol Pharmacol 1994; 46: 550–557.
Conti F, Melone M, De Biasi S. 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. J Comp Neurol 1998; 396: 51–63.
Dingledine R, Korn SJ. Gamma-aminobutyric acid uptake and the termination of inhibitory synaptic potentials in the rat hippocampal slice. J Physiol Lond 1985; 366: 387–409.
During MJ, Ryder KM, Spencer DD. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 1995; 376: 174–177.
Engel D, Pahner I, Schulze K et al. Plasticity of rat central inhibitory synapses through GABA metabolism. J Physiol Lond 2001; 535: 473–482.
Gadea A, Lopez-Colome AM. Glial transporters for glutamate, glycine, and GABA: II. GABA transporters. J Neurosci Res 2001; 63: 461–468.
Gaspary HL, Wang W, Richerson GB. Carrier-mediated GABA release activates GABA receptors on hippocampal neurons. J Neurophysiol 1998; 80: 270–281.
Honmou O, Kocsis JD, Richerson GB. Gabapentin potentiates the conductance increase induced by nipecotic acid in CAI pyramidal neurons in vitro. Epilepsy Res 1995; 20: 193–202.
Isaacson JS, Solis JM, Nicoll RA. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 1993; 10: 165–175.
Jung MJ, Palfreyman MG. Vigabatrin mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs. New York: Raven Press, 1995: 903–913.
Kanner BI, Schuldiner S. Mechanism of transport and storage of neurotransmitters. CRC Crit Rev Biochem 1987; 22: 1–38.
Krnjevic K, Morris ME, Reiffenstein RJ. Changes in extracellular Ca2* and K* activity accompanying hippocampal discharges. Can J Physiol Pharmacol 1980; 58: 579–582.
Lerma J, Herranz AS, Herreras O et al. In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res 1986; 384: 145–155.
Levi G, Raiteri M. Carrier-mediated release of neurotransmitters. Trends Neurosci 1993; 16: 415–419.
Levitan ES, Schofield PR, Burt DR et al. Structural and functional basis for GABAA receptor heterogeneity. Nature 1988; 335: 76–79.
Lu CC, Hilgemann DW. GAT1 (GABA:Na’:C1“) cotransport function. Steady state studies in giant Xenopus oocyte membrane patches. J Gen Physiol 1999; 114: 429–444.
Matskevitch I, Wagner CA, Stegen C et al. Functional characterization of the Betaine/ gamma-aminobutyric acid transporter BGT-1 expressed in Xenopus oocytes. J Biol Chem 1999; 274: 16709–16716.
Michelson HB, Wong RK. Excitatory synaptic responses mediated by GABAA receptors in the hippocampus. Science 1991; 253: 1420–1423.
Minelli A, Brecha NC, Karschin C et al. GAT-1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J Neurosci 1995; 15: 7734–7746.
Minelli A, DeBiasi S, Brecha NC et al. GAT-3, a high-affinity GABA plasma membrane transporter, is localized to astrocytic processes, and it is not confined to the vicinity of GABAergic synapses in the cerebral cortex. J Neurosci 1996; 16: 6255–6264.
Nusser Z, Mody I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol 2002; 87: 2624–2628.
Otis TS, Staley KJ, Mody I. Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release. Brain Res 1991; 545: 142–150.
Otsuka M, Obata K, Miyata Y et al. Measurement of gamma-aminobutyric acid in isolated nerve cells of cat central nervous system. J Neurochem 1971; 18: 287–295.
Overstreet LS, Westbrook GL. Paradoxical reduction of synaptic inhibition by vigabatrin. J Neurophysiol 2001; 86: 596–603.
Overstreet LS, Westbrook GL. Synapse density regulates independence at unitary inhibitory synapses. J Neurosci 2003; 23: 2618–2626.
Petroff OA, Behar KL, Mattson RH et al. Human brain gamma-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. J Neurochem 1996a; 67: 2399–2404.
Petroff OA, Rothman DL, Behar KL et al. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 19966; 39: 95–99.
Pietrini G, Suh YJ, Edelmann L et al. The axonal gamma-aminobutyric acid transporter GAT-1 is sorted to the apical membranes of polarized epithelial cells. J Biol Chem 1994; 269: 4668–4674.
Pin JP, Bockaert J. Two distinct mechanisms, differentially affected by excitatory amino acids, trigger GABA release from fetal mouse striatal neurons in primary culture. J Neurosci 1989; 9: 648–656.
Radian R, Ottersen OP, Storm-Mathisen J et al. Immunocytochemical localization of the GABA transporter in rat brain. J Neurosci 1990; 10: 1319–1330.
Ribak CE, Tong WM, Brecha NC. GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus. J Comp Neurol 1996; 367: 595–606.
Roepstorff A, Lambert JD. Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CAl neurones. Neurosci Lett 1992; 146: 131–134.
Rossi DJ, Hamann M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity as subunit GABAA receptors and glomerular geometry. Neuron 1998; 20: 783–795.
Saransaari P, Oja SS. Release of GABA and taurine from brain slices. Prog Neurobiol 1992; 38: 455–482.
Saxena NC, Macdonald RL. Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. Mol Pharmacol 1996; 49: 567–579.
Schwartz EA. Calcium-independent release of GABA from isolated horizontal cells of the toad retina. J Physiol Lond 1982; 323: 211–227.
Schwartz EA. Depolarization without calcium can release gamma-aminobutyric acid from a retinal neuron. Science 1987; 238: 350–355.
Somjen G, Giacchino JL. Potassium and calcium concentrations in interstitial fluid of hippocampal formation during paroxysmal responses. J Neurophysiol 1985; 53: 1098–1108.
Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995; 269: 977–981.
Stell BM, Mody I. Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons. J Neurosci 2002; 22:RC223.
Taylor CP, Gee NS, Su TZ et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998; 29: 233–249.
Thompson SM, Gahwiler BH. Effects of the GABA uptake inhibitor tiagabine on inhibitory synaptic potentials in rat hippocampal slice cultures. J Neurophysiol 1992; 67: 1698–1701.
Tossman U, Jonsson G, Ungerstedt U. Regional distribution and extracellular levels of amino acids in rat central nervous system. Acta Physiol Scand 1986; 127: 533–545.
Turner TJ, Goldin SM. Multiple components of synaptosomal [3H]-gamma-aminobutyric acid release resolved by a rapid superfusion system. Biochem 1989; 28: 586–593.
Welty DF, Schielke GP, Vartanian MG et al. Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate. Epilepsy Res 1993; 16: 175–181.
Whitworth TL, Quick MW. Upregulation of gamma-aminobutyric acid transporter expression: role of alkylated gamma-aminobutyric acid derivatives. Biochem Soc Trans 2001; 29: 736–741.
Williamson A, Telfeian AE, Spencer DD. Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis. J Neurophysiol 1995; 74: 378–387.
Wu Y, Wang W, Richerson GB. GABA transaminase inhibition induces spontaneous and enhances depolarization-evoked GABA efflux via reversal of the GABA transporter. J Neurosci 2001; 21: 2630–2639.
Wu Y, Wang W, Richerson GB. Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol 2003; 89: 2021–2034.
Zerangue N, Kavanaugh MP. Flux coupling in a neuronal glutamate transporter. Nature 1996; 383: 634–637.
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Richerson, G.B., Wu, Y. (2004). Role of the GABA Transporter in Epilepsy. In: Binder, D.K., Scharfman, H.E. (eds) Recent Advances in Epilepsy Research. Advances in Experimental Medicine and Biology, vol 548. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-6376-8_6
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DOI: https://doi.org/10.1007/978-1-4757-6376-8_6
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