Topiramate modulation of β 1- and β 3-homomeric GABA A receptors

Abstract

The broad spectrum anticonvulsant topiramate modulates multiple voltage-gated and ligand-gated channels, including γ-aminobutyric acid type A (GABA A) receptors. Previously, we found a strong β-subunit influence on the effects of topiramate on heteromeric GABA A receptors. Here, we tested the hypothesis that homomeric GABA A receptors comprised of either β 1- or β 3-subunits will contain a functional binding site for topiramate. For comparison, we also examined the effects of pentobarbital and loreclezole which exhibit β-subunit dependence as well. We expressed β 1- and β 3-homomeric receptors in Xenopus laevis oocytes and acquired electrophysiological responses using two-electrode voltage clamp techniques. Oocytes expressing β-homomers were insensitive to GABA and had hyperpolarized resting membrane potentials, decreased input resistances, increased holding currents and picrotoxin-induced outward currents consistent with the expression of non-ligand-mediated, spontaneous channel openings of β-homomers. Similar to picrotoxin, application of topiramate, pentobarbital and loreclezole inhibited β 1-homomers. In contrast, these compounds activated β 3-homomers. As with heteromeric receptors, topiramate and pentobarbital modulation of β 1- and β 3-homomers exhibited rebound currents indicating an open channel block or stabilization of desensitization. Interaction studies suggested competition between topiramate, loreclezole and pentobarbital for activation of β 3-homomers, whereas topiramate inhibitory actions were non-competitive with pentobarbital but competitive with loreclezole. In summary, β 1- and β 3-subunits have binding site(s) for topiramate that elicit functional effects with similarities to heteromeric receptor responses. From this foundation, contributions of residues and other subunits in binary and ternary heteromeric receptors can be explored to gain a complete understanding of topiramate actions on complex heteromeric GABA A receptors.