Received for publication October 12, 2004.
Revised January 14, 2005.
Accepted for publication January 18, 2005.

Benzodiazepines Affect Channel Opening of GABA_A Receptors Induced by Either Agonist Binding Site

Abstract

Benzodiazepines are widely used as anxiolytics, sedatives, muscle relaxants and anticonvulsants. They allosterically modulate -aminobutyric acid type A (GABA_A) receptors by increasing the apparent affinity of the agonist GABA to elicit chloride currents. Such an increase in apparent affinity of channel gating could either be due to an increase in affinity for GABA or due to a facilitation of channel opening. In the first case, conformation of the affected sites would have to be altered. In the second case, the affected sites are not necessarily altered, as diazepam could facilitate conformational changes leading to the open channel. It is controversial as to whether benzodiazepines affect only channel opening induced by occupation of one of the two agonist binding sites, or by both. We used receptors formed by concatenated subunits to selectively destroy one of the two agonist sites by point mutation. Both of the receptors harboring only one active agonist site could be stimulated by diazepam. We therefore present evidence that binding of diazepam can affect channel opening induced by either agonist binding site.

Key words: GABAA, GABAC, Func. analysis receptor/ion channel mutants, Benzodiazepines

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