Mol Pharmacol 2000 Jul 01;581:11-7.

Subunit-specific action of an anticonvulsant thiobutyrolactone on recombinant glycine receptors involves a residue in the M2 membrane-spanning region.

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The anticonvulsant alpha-ethyl, alpha-methyl-gamma-thiobutyrolactone (alphaEMTBL) potentiates the response to a submaximal concentration of glycine produced by receptors composed of human glycine alpha1-subunits but reduces the response of receptors composed of rat glycine alpha3-subunits. Both the potentiating and blocking actions of alphaEMTBL are reduced by higher concentrations of glycine. The subunit specificity of alphaEMTBL block is conferred by a residue in the second membrane-spanning region (M2), which is alanine in the alpha3-subunit (A254) and glycine in the alpha1-subunit. The mutation A254G in the alpha3-subunit removes blocking by alphaEMTBL and reveals potentiation. Picrotin, a picrotoxinin analog, blocks responses of receptors composed of either alpha1 or alpha3-subunits. Blocking of alpha3 receptors by picrotin is reduced in the presence of alphaEMTBL, indicating that the mechanisms interact at some point, but the mutation alpha3 A254G does not remove block by picrotin. However, mutation of a nearby residue alpha3 T258F does remove block by picrotin, picrotoxinin and alphaEMTBL. These observations suggest that alphaEMTBL and picrotin act on glycine alpha3 receptors to produce block by an allosteric mechanism that involves overlapping sets of residues in the M2 region. Coexpression of the alpha3-subunit with the beta-subunit of the glycine receptor also removes block by alphaEMTBL and reveals potentiation, suggesting that receptors containing either alpha3 or alpha1 glycine receptor subunits are potentiated in the adult brain.

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