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Journal of Neuroscience, Vol 10, 1719-1727, Copyright © 1990 by Society for Neuroscience
Physiological regulation of the picrotoxin receptor by gamma- butyrolactones and gamma-thiobutyrolactones in cultured hippocampal neurons
KD Holland, JA Ferrendelli, DF Covey and SM Rothman
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
We examined the effects of alkyl-substituted gamma-butyrolactones (GBLs),
and gamma-thiobutyrolactones (TBLs) on GABA currents in cultured,
voltage-clamped rat hippocampal neurons. Convulsant GBLs and TBLs reversiby
diminished GABA responses in a concentration-dependent manner.
beta-Ethyl-beta-methyl GBL (beta-EMGBL) completely abolished GABA responses
at 3 mM (IC(50)390 microM), while TBL and beta-ethyl- beta-methyl TBL
(beta-EMTBL)-induced inhibition of GABA currents was incomplete, saturating
at about 50% of control at 300 microM and 10 mM for beta-EMTBL and TBL,
respectively. beta-EMGBL and beta-EMTBL both increased the rate of decay of
inhibitory post-synaptic currents (IPSCs) and beta-EMGBL also decreased
IPSC peak amplitude. In contrast, the anticonvulsant
alpha-ethyl-alpha-methyl TBL (alpha-EMTBL) potentiated GABA currents at all
GABA concentrations tested; maximal potentiation was 190% of control at 1
mM alpha-EMTBL (EC50 102 microM). Another anticonvulsant
alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), potentiated responses to low
(0.5 microM) but not high (greater than or equal to 10 microM) GABA. It
also blocked the inhibitory effects of picrotoxin and beta-EMGBL and the
facilitative effect of alpha-EMTBL on responses to 30 microM GABA.
alpha-EMGBL did not interfere with other agents which augment GABA
currents. Both alpha-EMTBL and alpha-EMGBL decreased the rate of IPSC decay
without altering IPSC peak amplitude. None of these compounds had any
direct membrane effects. We propose that beta-alkyl GBLs diminish GABA
currents, and therefore, we hypothesize that these compounds are picrotoxin
receptor agonists. beta- Alkyl TBLs partially diminish GABA currents and
may be partial agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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