SITE-DIRECTED MUTAGENESIS OF THE HISTAMINE H-1-RECEPTOR REVEALS A SELECTIVE INTERACTION OF ASPARAGINE(207) WITH SUBCLASSES OF H-1-RECEPTOR AGONISTS

In this study we investigated the role of the threonine(203) and the a sparagine(207) residues in the fifth transmembrane domain of the guine a-pig histamine H-1-receptor by site-directed mutagenesis to non-funct ional alanines. Whereas the threonine(203) residue is not important fo r the action of histamine, the asparagine(207) residue appears to be i nvolved in the binding of the N-tau-nitrogen atom of histamine and its 2-methyl-analogue, For the 2-phenyl-analogue and non-imidazole H-1-re ceptor agonists, this residue is, however, not essential for binding. On the basis of this study we conclude that different histamine H-1-re ceptor agonists interact in different ways with the H-1-receptor prote in. Moreover, we speculate that the interaction with the N-pi-nitrogen atom is essential for H-1-receptor activation. (C) 1994 Academic Pres s, Inc.