Modification of benzodiazepine receptors supports the distinctive role of histidine residues

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The effect of selective protein modifying reagents was examined on benzodiazepine (BZ) receptors in synaptosomal membrane preparations of rat whole brain and cerebellum. The potency of diethyl pyrocarbonate, a histidine modifying reagent, to inactivate BZ receptor binding, correlated with the rank order of agonist-inverse agonist efficacies of BZ ligands, the binding of the partial inverse agonist [3H]Ro 15-4513 was inactivated least. Diethyl pyrocarbonate slightly enhanced the displacing potency of Ro 15-4513 and enhanced its binding in low concentrations (1-2 mM). Diazepam-sensitive and -insensitive components of [3H]Ro 15-4513 binding were separated in cerebellum. Diethyl pyrocarbonate inactivated the diazepam-sensitive component with a potency (IC50 = 1.8 mM) similar to that on the binding of other benzodiazepines, while the diazepam-insensitive component was resistant to diethyl pyrocarbonate. Tetranitromethane and 2,3-butanedione (diacetyl), reagents specific for tyrosine and arginine residues respectively, exerted concentration-dependent partial inactivation of [3H]Ro 15-4513 binding. The diazepam-insensitive component of cerebellar Ro 15-4513 binding was more sensitive to inactivation by diacetyl but less sensitive to inactivation by tetranitromethane. These findings are consistent with a distinctive role of histidine-101 in α1, α2, α3 and α5 subunits of the γ-aminobutyric acidA receptor complex and the His is replaced by an arginine residue in the α6 subunit of the diazepam-insensitive cerebellar benzodiazepine receptors. The only other point of the protein sequence where histidine residues conserved in α1, α2, α3 and α5 subunits are replaced in α6 is tyrosine-214 but this residue does not appear to contribute to benzodiazepine binding.

Original languageEnglish
Pages (from-to)57-62
Number of pages6
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Issue number1
Publication statusPublished - Sep 1 1992


  • 2,3-Butanedione
  • Benzodiazepine receptors (central)
  • Diethylpyrocarbonate
  • GABA receptors (α subunits)
  • Modification of receptors
  • [H]Ro 15-4513 binding

ASJC Scopus subject areas

  • Pharmacology

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