Discovery of a novel member of the histamine receptor family

We report the discovery, tissue distribution and pharmacological characteri zation of a novel receptor, which we have named H4. Like the three histamin e receptors reported previously (H1, H2, and H3), the H4 receptor is a G pr otein-coupled receptor and is most closely related to the H3 receptor, shar ing 58% identity in the transmembrane regions. The gene encoding the H4 rec eptor was discovered initially in a search of the GenBank databases as sequ ence fragments retrieved in a partially sequenced human genomic contig mapp ed to chromosome 18. These sequences were used to retrieve a partial cDNA c lone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revea led a 3.0-kb transcript in rat testis and intestine. Radioligand binding st udies indicated that the H4 receptor has a unique pharmacology and binds [H -3] histamine (K-d = 44 nM) and [H-3] pyrilamine (K-d = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mian serin) with moderate affinity (K-i range of 33-750 nM). Additionally, hista mine induced a rapid internalization of HA-tagged H4 receptors in transfect ed human embryonic kidney 293 cells.