Inhibition of uptake, steady-state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs

1 We have expressed the GABA transporter (GAT1) of mouse brain in Xenopus o ocytes and have investigated the effects bf four antiepileptic drugs, tiaga bine (TGB), vigabatrin (VGB), gabapentin (GBP) and valproate (VAL), on GAT1 transporter function by measurements of H-3-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 [H-3]-GABA by GAT1. Inhi bition at 50% is obtained for VGB, TGB, GBP, and VAL at concentrations of a bout 1 nM, 1 mu M, 50 mu M and 100 mu M, respectively. 3 However, GAT1-mediated steady-state and transient currents are nearly una ffected by VGB, GBP, and VAL at even five times higher concentrations. Only TGB blocks the uptake and steady-state and transient currents at micromola r concentrations. 4 VGB exhibits a complex interaction with GAT1; at concentrations about 1 n M, the inhibition of uptake is released, but at millimolar concentrations t he uptake is inhibited again, and also the GAT1-mediated current is finally inhibited at these concentrations with a K-I value of 0.5 mM. The concentr ation dependency of inhibition of uptake can be explained by two interactio n 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 ca n be attributed to the fact that GAT1 has the capability to operate in an e lectrogenic 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 eleva tion of the GABA concentration in the synaptic cleft, which will enhance sy naptic inhibition and thereby contribute to their antiepileptic effects.