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

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Abstract
1 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. 2 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. 3 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. 4 Guanylnucleotides displaced only 60% of specific [3H]-Nα-methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. 5 These data suggest that the H3-receptor can exist in different conformations for which thioperamide, but not Nα-methylhistamine and clobenpropit, show differential affinity. 6 The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3-receptor antagonism by thioperamide, are discussed.

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