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Inhibition of uptake, steady-state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs.
Eckstein-Ludwig U, Fei J, Schwarz W.
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1. We have expressed the GABA transporter (GAT1) of mouse brain in Xenopus oocytes and have investigated the effects of four antiepileptic drugs, tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP) and valproate (VAL), on GAT1 transporter function by measurements of 3H-labelled GABA uptake and GAT1-mediated currents. 2. Not only TGB, a well-known inhibitor of GAT1-mediated transport, but also the other drugs efficiently inhibit the uptake of [3H]-GABA by GAT1. Inhibition at 50% is obtained for VGB, TGB, GBP, and VAL at concentrations of about 1 nM, 1 microM, 50 microM and 100 microM, respectively. 3. However, GAT1-mediated steady-state and transient currents are nearly unaffected by VGB, GBP, and VAL at even five times higher concentrations. Only TGB blocks the uptake and steady-state and transient currents at micromolar concentrations. 4. VGB exhibits a complex interaction with GAT1; at concentrations about 1 nM, the inhibition of uptake is released, but at millimolar concentrations the uptake is inhibited again, and also the GAT1-mediated current is finally inhibited at these concentrations with a KI value of 0.5 mM. The concentration dependency of inhibition of uptake can be explained by two interaction sites with different affinities, a blocking site and a transport site. 5. The differences in effects of VAL, GBP, and VGB on uptake and currents can be attributed to the fact that GAT1 has the capability to operate in an electrogenic mode without uptake of GABA. We suggest that inhibition occurs only when GAT1 operates in the GABA-uptake mode. 6. The inhibition of GABA uptake by these four drugs will result in an elevation of the GABA concentration in the synaptic cleft, which will enhance synaptic inhibition and thereby contribute to their antiepileptic effects.
Barish,
A transient calcium-dependent chloride current in the immature Xenopus oocyte.
1983, Pubmed,
Xenbase
Barish,
A transient calcium-dependent chloride current in the immature Xenopus oocyte.
1983,
Pubmed
,
Xenbase Borden,
GABA transporter heterogeneity: pharmacology and cellular localization.
1996,
Pubmed Cammack,
Channel behavior in a gamma-aminobutyrate transporter.
1996,
Pubmed Cammack,
A GABA transporter operates asymmetrically and with variable stoichiometry.
1994,
Pubmed DeFelice,
Pore models for transporters?
1996,
Pubmed Golan,
GABA metabolism controls inhibition efficacy in the mammalian CNS.
1996,
Pubmed Guastella,
Cloning and expression of a rat brain GABA transporter.
1990,
Pubmed
,
Xenbase Jackson,
Acute effects of gamma-vinyl GABA (vigabatrin) on hippocampal GABAergic inhibition in vitro.
1994,
Pubmed Lafaire,
Voltage dependence of the rheogenic Na+/K+ ATPase in the membrane of oocytes of Xenopus laevis.
1986,
Pubmed
,
Xenbase Lambert,
Analysis of the kinetics of synaptic inhibition points to a reduction in GABA release in area CA1 of the genetically epileptic mouse, El.
1996,
Pubmed Läuger,
Fluctuations of barrier structure in ionic channels.
1980,
Pubmed Leach,
Neurochemical actions of vigabatrin and tiagabine alone and in combination in mouse cortex.
1997,
Pubmed Leach,
Effects of tiagabine and vigabatrin on GABA uptake into primary cultures of rat cortical astrocytes.
1996,
Pubmed Liu,
Effect of mutation of glycosylation sites on the Na+ dependence of steady-state and transient currents generated by the neuronal GABA transporter.
1998,
Pubmed
,
Xenbase Liu,
Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain [corrected].
1993,
Pubmed
,
Xenbase Löscher,
New visions in the pharmacology of anticonvulsion.
1998,
Pubmed Löscher,
Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model.
1989,
Pubmed Lücke,
Gabapentin potentiation of the antiepileptic efficacy of vigabatrin in an in vitro model of epilepsy.
1998,
Pubmed Mager,
Ion binding and permeation at the GABA transporter GAT1.
1996,
Pubmed
,
Xenbase Mager,
Steady states, charge movements, and rates for a cloned GABA transporter expressed in Xenopus oocytes.
1993,
Pubmed
,
Xenbase Miledi,
A calcium-dependent transient outward current in Xenopus laevis oocytes.
1982,
Pubmed
,
Xenbase Nelson,
Cloning of the human brain GABA transporter.
1990,
Pubmed Risso,
Sodium-dependent GABA-induced currents in GAT1-transfected HeLa cells.
1996,
Pubmed Roepstorff,
Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CA1 neurones.
1992,
Pubmed Schloss,
Neurotransmitter transporters. A novel family of integral plasma membrane proteins.
1992,
Pubmed Schmalzing,
Up-regulation of sodium pump activity in Xenopus laevis oocytes by expression of heterologous beta 1 subunits of the sodium pump.
1991,
Pubmed
,
Xenbase Schousboe,
Stereoselective uptake of the GABA-transaminase inhibitors gamma-vinyl GABA and gamma-acetylenic GABA into neurons and astrocytes.
1986,
Pubmed Velísková,
Developmental regulation of regional functionality of substantial nigra GABAA receptors involved in seizures.
1996,
Pubmed
