Is the benzodiazepine receptor coupled to a chloride anion channel?

Abstract

HIGH affinity saturable binding sites for benzodiazepines (BZs) in mammalian brain have been described1. These sites show stereospecificity, organ and subcellular distribution, and structure–activity relationships reminiscent of other synaptic membrane receptors which have been characterised by ligand binding2,3. The BZ receptor is so highly selective that no known putative neurotransmitters interact with it, thus raising the possibility that the brain contains another unidentified endogenous ligand4,5. Recently, Tallman et al. have reported that γ-aminobutyric acid (GABA) specifically enhances the binding of 3H-diazepam to rat brain membranes6. Considerable biochemical and neurophysiological evidence suggests that GABA may be intimately involved in the mechanism of action of BZs7–10,18. In several neurotransmitter systems, ions seem to have specific effects on the binding of synaptic receptor ligands, presumably because of the intimate association of the receptor with an ion channel. For example, binding of opiate agonists and antagonists is differentially affected by sodium ion11, and Na+ conductance is altered by opiate agonists12. Similarly, specific effects of anions on the receptors for strychnine13 and GABA14 are correlated with observations that the neurophysiological action of these receptors is dependent on alterations in chloride ion conductance15,16. We now report the specific effect of chloride and other anions in enhancing BZ binding to its receptor. We infer that the BZ receptor (recognition site) may be closely associated with a chloride ion channel which is also closely linked to the GABA-recognition site.