Modulation of the Benzodiazepine-GABA Receptor Chloride Ionophore Complex by Multiple Allosteric Sites: Evidence for a Barbiturate “Receptor”
The discovery of specific recognition sites (receptors) for benzodiazepines in the central nervous system has resulted in a better understanding of the molecular pharmacology of benzodiazepines, barbiturates, and related compounds. Within the past 5 years it has become apparent that the benzodiazepine receptor is one component of a “supramolecular complex” consisting of multiple allosteric recognition sites which play a critical role in the regulation of transmembrane potential. Both neurochemical and electrophysiological studies support the notion that occupation of either the benzodiazepine-GABA receptor complex or distinct, allosteric sites for compounds such as barbiturates and cage convulsants (which are probably located on or near the chloride ionophore) can regulate the properties of this chloride channel. This chapter will review neurochemical evidence that demonstrates a functional coupling of the recognition components of the benzo-diazepine-GABA receptor chloride ionophore complex (supramolecular complex) and summarize recent findings from our laboratory demonstrating that the “effector” component of this complex, the chloride ionophore, is rapidly altered by stress.
KeywordsChloride Channel Supramolecular Complex Apparent Affinity Naive Animal Gaba Binding
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- Biggio G (1983) The actions of stress, β-earbolines, diazepam, and Ro 15-1788 on GABA receptors in the rat brain. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven, New York, pp 105–120Google Scholar
- Gavish M, Snyder SH (1981) Gamma-aminobutyric acid and benzodiazepine receptors: Copurification and characterization. Proc Natl Acad Sci USA 78: 1939–1942Google Scholar
- Haefely W, Pole P (1983) Electrophysiological studies on the interaction of anxiolytic drugs with GABAergic mechanisms. In: Malick J, Enna S, Yamamura H (eds) Anxiolytics: neurochemical, behavioral and clinical perspectives. Raven, New York, pp 113–145Google Scholar
- Havoundjian H, Paul SM, Skolnick P (1985 a) Rapid, stress induced modulation of the benzodiazepine receptor coupled chloride ionophore. Brain Res 375: 401–406Google Scholar
- Havoundjian H, Paul SM, Skolnick P (1985 b) Acute, stress-induced changes in the benzodiazepine-GABA receptor complex are confined to the chloride ionophore. J Pharmacol Exp Ther 237: 787–793Google Scholar
- Mohler H, Schoch P, Haring P, Takacs B, Stahli C (1984) A purified GABA/benzodiazepine receptor: biochemical, pharmacological and immunological characterization. Clin Neuropharmacol 7 [Suppl 1]:S-307Google Scholar
- Schwartz R, Jackson J, Weigart D, Skolnick P, Paul SM (1985 a) Characterization of barbiturate-stimulated chloride efflux from rat brain synaptoneurosomes. J Neurosci (in press)Google Scholar
- Schwartz R, Skolnick P, Seale T, Paul SM (1985 b) Demonstration of GABA/barbiturate-receptor-mediated chloride transport in rat brain synaptoneurosomes: a functional assay of GABA receptor-effector coupling. In: Biggio G, Costa E (eds) Advances in biochemical psychopharmacology. GABAergic transmission and anxiety. Raven, New York (in press)Google Scholar
- Squires RF, Casida JE, Richardson M, Saederup E (1983) 35S t-Butylbicyclophosphorothionate binds with high affinity to brain specific sites couples to gamma-aminobutyric acid-A and ion recognition sites. Mol Pharmacol 23: 326–336Google Scholar
- Ticku MK, Ban M, Olsen RW (1978 a) Binding of [3H]a-dihydropicrotoxinin, a gamma-aminobutyric acid synaptic antagonist, to rat brain membranes. Mol Pharmacol 14: 391–402Google Scholar
- Ticku MK, Van Ness FC, Haycock JW, Levy WB, Olsen RW (1978 b) Dihydropicrotoxinin binding sites in rat brain: comparison to GABA receptors. Brain Res 150: 642–647Google Scholar