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

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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 (KD = 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., KD > 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.