Distinct pharmacology of rat and human histamine H-3 receptors: role of two amino acids in the third transmembrane domain

Starting from the sequence of the human histamine H-3 receptor (hH(3)R) cDN A, we have cloned the corresponding rat cDNA. Whereas the two deduced prote ins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed di stinct affinities. Thioperamide and ciproxifan were about 10 fold more pote nt at the rat than at the human receptor, whereas FUB 349 displayed a rever se preference. Histamine, (R)alpha -methylhistamine, proxyfan or clobenprop it were nearly equipotent at H-3 receptors of both species. The inverse dis crimination patterns of ciproxifan and FUB 349 were partially changed by mu tation of one amino acid (V122A), and fully abolished by mutation of two am ino acids (A119T and V122A), in TM3 of the rH(3)R located in the vicinity o f Asp(114) purported to salt-link the ammonium group of histamine. Therefor e, these two residues appear to be responsible for the distinct pharmacolog y of the H3R in the two species.