Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) 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 H(3) receptor cDNA. Expression of the full-length human GPCR105 in cells confers the ability to bind [(3)H]histamine with high affinity (K(D) = 5 nM). GPCR105 is pharmacologically similar to the histamine H(3) 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 microM) 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.
Liu
C
C
The R. W. Johnson Pharmaceutical Research Institute, San Diego, California, USA.
Ma
X
X
Jiang
X
X
Wilson
S J
SJ
Hofstra
C L
CL
Blevitt
J
J
Pyati
J
J
Li
X
X
Chai
W
W
Carruthers
N
N
Lovenberg
T W
TW
D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D001853:Bone Marrow / Q000378:metabolism / Q000502:physiology*; D003001:Cloning, Molecular; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D008761:Methylhistamines / Q000494:pharmacology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014316:Tritium
C418607:HRH4 protein, human; D008761:Methylhistamines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D014316:Tritium; D006632:Histamine; D000262:Adenylyl Cyclases; C048140:N-methylhistamine