Topiramate (TPM) is an anticonvulsant of novel chemical structure whose mechanism of action remains elusive. Reports of TPM modulation of ligand- and voltage-gated ion channel functions are variable and often inconsistent. In fact, TPM has been found to produce enhancement, inhibition, and no effect on GABA-currents of cultured neurons and GABA(A) receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABA(A) receptors, multiple combinations of recombinant GABA(A) receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the beta subunit isoform co-expressed in heteromeric GABA(A) receptors. TPM potentiated and directly activated heteromeric receptors containing either beta(2) or beta(3) subunit. TPM's direct activation was most effective on receptors comprised of alpha(4)beta(3)gamma(2S) subunits and activated approximately 74% of the peak GABA-current. TPM modulation of beta(1)-containing heteromeric receptors depended on the co-expressed alpha subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the beta subunit present. These results suggest that the effects of TPM on GABA(A) receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.