Subunit selectivity of topiramate modulation of heteromeric GABAA receptors

Timothy Simeone, Karen S. Wilcox, H. Steve White

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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 GABAA receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABAA receptors, multiple combinations of recombinant GABAA receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the β subunit isoform co-expressed in heteromeric GABAA receptors. TPM potentiated and directly activated heteromeric receptors containing either β2 or β3 subunit. TPM's direct activation was most effective on receptors comprised of α4β3γ2S subunits and activated ∼74% of the peak GABA-current. TPM modulation of β1-containing heteromeric receptors depended on the co-expressed α subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the β subunit present. These results suggest that the effects of TPM on GABAA receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.

Original languageEnglish
Pages (from-to)845-857
Number of pages13
JournalNeuropharmacology
Volume50
Issue number7
DOIs
StatePublished - Jun 2006

Fingerprint

GABA-A Receptors
gamma-Aminobutyric Acid
Oocytes
Protein Isoforms
topiramate
Ligand-Gated Ion Channels
Xenopus laevis
Xenopus
Nervous System Diseases
Anticonvulsants
Neurons

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Subunit selectivity of topiramate modulation of heteromeric GABAA receptors. / Simeone, Timothy; Wilcox, Karen S.; White, H. Steve.

In: Neuropharmacology, Vol. 50, No. 7, 06.2006, p. 845-857.

Research output: Contribution to journalArticle

Simeone, Timothy ; Wilcox, Karen S. ; White, H. Steve. / Subunit selectivity of topiramate modulation of heteromeric GABAA receptors. In: Neuropharmacology. 2006 ; Vol. 50, No. 7. pp. 845-857.
@article{6a5ca813330040c6a758e3cd2b8f3644,
title = "Subunit selectivity of topiramate modulation of heteromeric GABAA receptors",
abstract = "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 GABAA receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABAA receptors, multiple combinations of recombinant GABAA receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the β subunit isoform co-expressed in heteromeric GABAA receptors. TPM potentiated and directly activated heteromeric receptors containing either β2 or β3 subunit. TPM's direct activation was most effective on receptors comprised of α4β3γ2S subunits and activated ∼74{\%} of the peak GABA-current. TPM modulation of β1-containing heteromeric receptors depended on the co-expressed α subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the β subunit present. These results suggest that the effects of TPM on GABAA receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.",
author = "Timothy Simeone and Wilcox, {Karen S.} and White, {H. Steve}",
year = "2006",
month = "6",
doi = "10.1016/j.neuropharm.2005.12.006",
language = "English",
volume = "50",
pages = "845--857",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "7",

}

TY - JOUR

T1 - Subunit selectivity of topiramate modulation of heteromeric GABAA receptors

AU - Simeone, Timothy

AU - Wilcox, Karen S.

AU - White, H. Steve

PY - 2006/6

Y1 - 2006/6

N2 - 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 GABAA receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABAA receptors, multiple combinations of recombinant GABAA receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the β subunit isoform co-expressed in heteromeric GABAA receptors. TPM potentiated and directly activated heteromeric receptors containing either β2 or β3 subunit. TPM's direct activation was most effective on receptors comprised of α4β3γ2S subunits and activated ∼74% of the peak GABA-current. TPM modulation of β1-containing heteromeric receptors depended on the co-expressed α subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the β subunit present. These results suggest that the effects of TPM on GABAA receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.

AB - 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 GABAA receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABAA receptors, multiple combinations of recombinant GABAA receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the β subunit isoform co-expressed in heteromeric GABAA receptors. TPM potentiated and directly activated heteromeric receptors containing either β2 or β3 subunit. TPM's direct activation was most effective on receptors comprised of α4β3γ2S subunits and activated ∼74% of the peak GABA-current. TPM modulation of β1-containing heteromeric receptors depended on the co-expressed α subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the β subunit present. These results suggest that the effects of TPM on GABAA receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.

UR - http://www.scopus.com/inward/record.url?scp=33646693680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646693680&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2005.12.006

DO - 10.1016/j.neuropharm.2005.12.006

M3 - Article

C2 - 16490221

AN - SCOPUS:33646693680

VL - 50

SP - 845

EP - 857

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 7

ER -