Discovery of a novel member of the histamine receptor family.
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.
Nguyen
T
T
The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Shapiro
D A
DA
George
S R
SR
Setola
V
V
Lee
D K
DK
Cheng
R
R
Rauser
L
L
Lee
S P
SP
Lynch
K R
KR
Roth
B L
BL
O'Dowd
B F
BF
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
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