Referenced in: none

Automatically associated channels: Kv10.1

Title: Modification of benzodiazepine receptors supports the distinctive role of histidine residues.

Authors: G Maksay

Journal, date & volume: Eur. J. Pharmacol., 1992 Sep 1 , 227, 57-62

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/1330639

Abstract
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 alpha 1, alpha 2, alpha 3 and alpha 5 subunits of the gamma-aminobutyric acidA receptor complex and the His is replaced by an arginine residue in the alpha 6 subunit of the diazepam-insensitive cerebellar benzodiazepine receptors. The only other point of the protein sequence where histidine residues conserved in alpha 1, alpha 2, alpha 3 and alpha 5 subunits are replaced in alpha 6 is tyrosine-214 but this residue does not appear to contribute to benzodiazepine binding.