Differential effect of sodium ions and guanine nucleotides on the binding of thioperamide and clobenpropit to histamine H3‐receptors in rat cerebral cortical membranes

Abstract

Conflicting reports in the literature over heterogeneity (West et al., 1990) or homogeneity (Arrang et al., 1990) of histamine H3‐receptor binding sites may be attributed to the use of different incubation conditions. In the present study we have investigated the extent to which the binding of H3‐receptor ligands to rat cerebral cortical membranes can be modified by both sodium ions and guanine nucleotides. The H3‐selective antagonist, thioperamide, discriminated between two specific binding sites for [3H]‐Nα‐methylhistamine (IC50 1 = 2.75 ± 0.87 nm, IQ50 2 = 101.6 ± 12.0 nm, % site 1 = 24 ± 2%) in 50 mm Tris HCl buffer, but showed homogeneity of binding in 50 mm Na/K phosphate buffer. Sodium ions markedly altered the binding characteristics of thioperamide (i.e. heterogeneity was lost and IC50 value shifted towards the high affinity site). The competition curves for a second H3‐antagonist, clobenpropit and the H3‐agonist Nα‐methylhistamine however, were unaltered in the presence of sodium ions. Guanylnucleotides displaced only 60% of specific [3H]‐Nα‐methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. These data suggest that the H3‐receptor can exist in different conformations for which thioperamide, but not Nα‐methylhistamine and clobenpropit, show differential affinity. The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3‐receptor antagonism by thioperamide, are discussed. 1995 British Pharmacological Society