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Vol. 58, Issue 1, 11-17, July 2000

Subunit-Specific Action of an Anticonvulsant Thiobutyrolactone on Recombinant Glycine Receptors Involves a Residue in the M2 Membrane-Spanning Region

Joe Henry Steinbach, John Bracamontes, Li Yu, Pengnian Zhang, and Douglas F. Covey

Departments of Anesthesiology (J.H.S., J.B., L.Y., P.Z.) and Molecular Biology & Pharmacology (D.F.C.), Washington University School of Medicine, St. Louis, Missouri

The anticonvulsant alpha -ethyl, alpha -methyl-gamma -thiobutyrolactone (alpha EMTBL) potentiates the response to a submaximal concentration of glycine produced by receptors composed of human glycine alpha 1-subunits but reduces the response of receptors composed of rat glycine alpha 3-subunits. Both the potentiating and blocking actions of alpha EMTBL are reduced by higher concentrations of glycine. The subunit specificity of alpha EMTBL block is conferred by a residue in the second membrane-spanning region (M2), which is alanine in the alpha 3-subunit (A254) and glycine in the alpha 1-subunit. The mutation A254G in the alpha 3-subunit removes blocking by alpha EMTBL and reveals potentiation. Picrotin, a picrotoxinin analog, blocks responses of receptors composed of either alpha 1 or alpha 3-subunits. Blocking of alpha 3 receptors by picrotin is reduced in the presence of alpha EMTBL, indicating that the mechanisms interact at some point, but the mutation alpha 3 A254G does not remove block by picrotin. However, mutation of a nearby residue alpha 3 T258F does remove block by picrotin, picrotoxinin and alpha EMTBL. These observations suggest that alpha EMTBL and picrotin act on glycine alpha 3 receptors to produce block by an allosteric mechanism that involves overlapping sets of residues in the M2 region. Coexpression of the alpha 3-subunit with the beta -subunit of the glycine receptor also removes block by alpha EMTBL and reveals potentiation, suggesting that receptors containing either alpha 3 or alpha 1 glycine receptor subunits are potentiated in the adult brain.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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