Topiramate modulation of β1- and β3-homomeric GABAA receptors

The broad spectrum anticonvulsant topiramate modulates multiple voltage-gated and ligand-gated channels, including γ-aminobutyric acid type A (GABAA) receptors. Previously, we found a strong β-subunit influence on the effects of topiramate on heteromeric GABAA receptors. Here, we tested the hypothesis that homomeric GABAA receptors comprised of either β1- or β3-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 β1- and β3-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 β1-homomers. In contrast, these compounds activated β3-homomers. As with heteromeric receptors, topiramate and pentobarbital modulation of β1- and β3-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 β3-homomers, whereas topiramate inhibitory actions were non-competitive with pentobarbital but competitive with loreclezole. In summary, β1- and β3-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 GABAA receptors.

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