Discovery of a novel member of the histamine receptor family

Mol Pharmacol. 2001 Mar;59(3):427-33. doi: 10.1124/mol.59.3.427.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amitriptyline / pharmacology
  • Antidepressive Agents, Tricyclic / pharmacology
  • Antipsychotic Agents / pharmacology
  • Chlorpromazine / pharmacology
  • Dose-Response Relationship, Drug
  • Histamine / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Weight
  • Radioligand Assay
  • Receptors, G-Protein-Coupled*
  • Receptors, Histamine / drug effects
  • Receptors, Histamine / genetics*
  • Receptors, Histamine / metabolism
  • Receptors, Histamine H3 / chemistry
  • Receptors, Histamine H4
  • Sequence Homology, Amino Acid
  • Tissue Distribution


  • Antidepressive Agents, Tricyclic
  • Antipsychotic Agents
  • HRH4 protein, human
  • Membrane Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Receptors, Histamine H4
  • Amitriptyline
  • Histamine
  • Chlorpromazine