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Molecular Mechanisms Mediating the Action of Diazepam on GABA Receptors

Published online by Cambridge University Press:  29 January 2018

E. Costa ,
A. Guidotti  and
G. Toffano
E. Costa
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
A. Guidotti
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
G. Toffano
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
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Summary

Two types of crude synaptic membranes have been prepared which differ in their kinetic properties to bind 3H-GABA in a Na+-free medium. One type (B) has one type of receptor (affinity or KD about 0.2 μM), the other type (A) has two populations of receptors which have a high (0.16 μM) and a low (.02 μM) KD for GABA binding. This difference is due to the presence of a selective endogenous inhibitor of the high affinity receptor for GABA, a thermostable protein of about 15,000 molecular weight. Inhibitor action is counteracted by diazepam (7 x 10-7M), competitively. Clonazepam is more active but chlordiazepoxide is less active than diazepam. Two enantiomers of a benzodiazepine were studied. One of them is endowed with anxiolytic activity and nullifies the action of the endogenous inhibitor on high affinity GABA binding, the other is devoid of anxiolytic activity and is inactive against the inhibitor. The endogenous protein inhibitor also competitively blocks the high affinity binding of 3H-diazepam to Type A membranes. It is concluded that the endogenous inhibitor and diazepam act on the same receptor; and suggested that the endogenous inhibitor may be the natural ligand for the brain receptors that bind benzodiazepines with high affinity.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 133 , Issue 3 , September 1978 , pp. 239 - 248
Copyright
Copyright © Royal College of Psychiatrists, 1978 

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