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Differential regulation of γ‐aminobutyric acid receptor channels by diazepam and phenobarbital
Author(s) -
Twyman Roy E.,
Rogers Carl J.,
Macdonald Robert L.
Publication year - 1989
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410250302
Subject(s) - phenobarbital , bursting , diazepam , gabaa receptor , chloride channel , chemistry , gaba receptor , anticonvulsant , electrophysiology , pharmacology , patch clamp , receptor , biophysics , neuroscience , medicine , endocrinology , biology , biochemistry , epilepsy
The anticonvulsant activity of diazepam and phenobarbital may be mediated in part by enhancement of inhibition involving γ‐aminobutyric acid (GABA). While both diazepam and phenobarbital increase GABA receptor chloride current, they may have different mechanisms of action, since they bind to different sites on the GABA receptor—chloride channel complex. We used the patch clamp technique to compare the effects of diazepam and phenobarbital on single GABA receptor currents. Outside‐out patches were obtained from mouse spinal cord neurons grown in cell culture for 2 to 4 weeks. GABA (2 μM) evoked single channel currents that occurred as single brief openings or in bursts of multiple openings. Diazepam (20 nM) and phenobarbital (500 μM) both increased the GABA receptor current by increasing mean open time without altering channel opening frequency. However, the temporal grouping of openings into bursts suggested that the enhancement occurred via different mechanisms. Diazepam increased the frequency of bursting GABA receptor currents with minimal effect on the duration of bursts. Phenobarbital increased the duration of bursting GABA receptor currents without altering the frequency of bursts. These results suggest that diazepam binds to a site that may enhance single channel burst frequency by increasing the affinity of GABA binding, while phenobarbital may stabilize the bursting open state of the channel by binding to a different modulatory site at or near the chloride channel.