title: Discovery of a novel member of the histamine receptor family.
abstract: We report the discovery, tissue distribution and pharmacological characterization of a novel receptor, which we have named H4. Like the three histamine receptors reported previously (H1, H2, and H3), the H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18. These sequences were used to retrieve a partial cDNA clone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revealed a 3.0-kb transcript in rat testis and intestine. Radioligand binding studies indicated that the H4 receptor has a unique pharmacology and binds [(3)H]histamine (K(d) = 44 nM) and [(3)H]pyrilamine (K(d) = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mianserin) with moderate affinity (K(i) range of 33-750 nM). Additionally, histamine induced a rapid internalization of HA-tagged H4 receptors in transfected human embryonic kidney 293 cells.
authors.affiliation: The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.forename: D A
authors.initials: DA
authors.lastname: Shapiro
authors.forename: S R
authors.initials: SR
authors.lastname: George
authors.forename: V
authors.initials: V
authors.lastname: Setola
authors.forename: D K
authors.initials: DK
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Cheng
authors.forename: L
authors.initials: L
authors.lastname: Rauser
authors.forename: S P
authors.initials: SP
authors.lastname: Lee
authors.forename: K R
authors.initials: KR
authors.lastname: Lynch
authors.forename: B L
authors.initials: BL
authors.lastname: Roth
authors.forename: B F
authors.initials: BF
authors.lastname: O'Dowd
mesh_terms: D000595:Amino Acid Sequence; D000639:Amitriptyline / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000737:chemistry; D000074040:Receptors, Histamine H4; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
chemical_list: D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; C418607:HRH4 protein, human; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D000639:Amitriptyline; D006632:Histamine; D002746:Chlorpromazine