DUAL MODULATION OF THE GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR IONOPHORE BY ALKYL-SUBSTITUTED GAMMA-BUTYROLACTONES

Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolact ones exhibit convulsant or anticonvulsant activity, depending on the a lkyl substituents, alpha-Substituted lactones with small alkyl substit uents are anticonvulsant and potentiate gamma-aminobutyric acid (GABA) -mediated chloride currents, whereas beta-substituted compounds are us ually convulsant and block GABA(A) currents. We have now found that th is distinction is not so clear-cut, in that some compounds can both bl ock and augment GABA(A) currents, but with different time courses. For example, alpha,alpha-diisopropyl-GBL (alpha-DIGBL) potentiates exogen ous GABA currents in cultured rat hippocampal neurons but diminishes G ABA-mediated inhibitory postsynaptic currents. A more detailed analysi s demonstrates a triphasic effect of alpha-DIGBL on GABA currents, wit h a rapid inhibitory phase, a slower potentiating phase, and then an ' 'off response'' when the GABA/alpha-DIGBL perfusion is stopped. Thus, alpha-DIGBL can inhibit and potentiate GABA currents with kinetically different time courses. Inhibition is more rapid, but at steady state potentiation dominates. Using a simplified model of the GABA(A) recept or/ionophore, we have simulated our experimental observations with alp ha-DIGBL. Another lactone, beta-ethyl-beta-methyl-gamma-thiobutyrolact one, also has dual actions, with inhibition predominating at low conce ntrations and potentiation predominating at high concentrations. We pr opose two distinct GBL modulatory sites on the GABA(A) receptor, i.e., an inhibitory ''picrotoxin'' site and an enhancing ''lactone site.'' New information on the structure of the GABA(A) receptor/ionophore may allow the molecular dissection of these two sites.