Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow

Histamine is a multifunctional hormone that regulates smooth muscle contraction in the airways, acid secretion in the gut, and neurotransmitter release in the central nervous system through three well characterized receptor subtypes, H-1,H-2,H-3, respectively. As part of a directed effort to discover novel G-protein-coupled receptors through homology searching of genomic databases, we identified a partial clone (GPCR105) that had significant homology to the recently identified histamine H3 receptor cDNA. Expression of the full-length human GPCR105 in cells confers the ability to bind [H-3] histamine with high affinity (K-D = 5 nM). GPCR105 is pharmacologically similar to the histamine H3 receptor in that it binds many of the known H-3 agonists and antagonists, albeit with a different rank order of affinity/potency. GPCR105 does not bind (i. e., K-D. > 10 muM) all tested H-1 and H-2 receptor antagonists such as diphenhydramine, loratadine, ranitidine, and cimetidine, but has modest affinity for the H-2 receptor agonist, dimaprit (377 nM). Whereas the H-3 receptor is expressed almost exclusively in nervous tissues, GPRC105 is expressed primarily in bone marrow and eosinophils. Together, these data demonstrate that GPCR105 is a novel histamine receptor structurally and pharmacologically related to the H-3 receptor. However, its unique expression profile and physiological role suggest that GPCR105 is a fourth histamine receptor subtype (H-4) and may be a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.