Cloning and Pharmacological Characterization of a Fourth Histamine Receptor (H₄) Expressed in Bone Marrow

Abstract

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, H₁, H₂, H₃, 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 [³H]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 H₃ agonists and antagonists, albeit with a different rank order of affinity/potency. GPCR105 does not bind (i.e., K_D > 10 μM) all tested H₁ and H₂ receptor antagonists such as diphenhydramine, loratadine, ranitidine, and cimetidine, but has modest affinity for the H₂ receptor agonist, dimaprit (377 nM). Whereas the H₃ 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 H₃ receptor. However, its unique expression profile and physiological role suggest that GPCR105 is a fourth histamine receptor subtype (H₄) and may be a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.