Histamine

Overview: Histamine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Histamine Receptors, see Hill et al., 1997) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues (see Hill et al., 1997).

Nomenclature	H1	H2	H3	H4
Ensembl ID	ENSG00000171088	ENSG00000168546	ENSG00000146013	ENSG00000125861
Principal transduction	Gq/11	Gs	Gi/o	Gi/o
Selective agonists	Histaprodifen, Nτ-methylhistaprodifen	Amthamine	Methimepip (Kitbunnadaj et al., 2005), immethridine (Kitbunnadaj et al., 2004)	Clobenpropit, 4-methylhistamine, VUF8430 (Lim et al., 2006)
Selective antagonists	Triprolidine (9.9), mepyramine (9.1)	Tiotidine (7.8), ranitidine (7.1)	Clobenpropit (9.9), iodophenpropit (9.6), A331440 (8.5, Hancock et al., 2004), thioperamide (8.4)	JNJ7777120 (8.1)
Probes	[3H]-Mepyramine (1 nM), [11C]-Mepyramine, [11C]-doxepin	[3H]-Tiotidine (15 nM), [125I]-iodoaminopotentidine (0.3 nM)	[3H]-R-α-Methylhistamine (0.5 nM), [3H]-Nα-methylhistamine (2 nM), [125I]-iodophenpropit (0.6 nM), [125I]-iodoproxyfan (0.06 nM)	[3H]-JNJ7777120 (3.6 nM)

Histaprodifen and N^τ-methylhistaprodifen are reduced efficacy agonists. The H₄ receptor appears to exhibit broadly similar pharmacology to the H₃ receptor for imidazole-containing ligands, although R-α-methylhistamine and N-α-methylhistamine are less potent, while clobenpropit acts as a reduced efficacy agonist (Nakamura et al., 2000; Oda et al., 2000; Liu et al., 2001; Nguyen et al., 2001; Zhu et al., 2001). Moreover, 4-methylhistamine is identified as a high-affinity, full agonist for the human H₄ receptor (Lim et al., 2005). [³H]-Histamine has been used to label the H₄ receptor in heterologous expression systems.

Further Reading

Akdis CA, Simons FE (2006). Histamine receptors are hot in immunopharmacology. Eur J Pharmacol533: 69–76.

Esbenshade TA, Fox GB, Cowart MD (2006). Histamine H₃ receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol Interv6: 77–88.

Haas HL, Sergeeva OA, Selbach O (2008). Histamine in the nervous system. Physiol Rev88: 1183–1241.

Hancock AA (2006). The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H₃ antagonists/inverse agonists. Biochem Pharmacol71: 1103–1113.

Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM et al. (1997). International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev49: 253–278.

Leurs R, Bakker RA, Timmerman H, de Esch I (2005). The histamine H₃ receptor: from gene cloning to H₃ receptor drugs. Nat Rev Drug Discovery4: 107–120.

Leurs R, Chazot PL, Shenton FC, Lim HD, de Esch IJ (2009). Molecular and biochemical pharmacology of the histamine H4 receptor. Br J Pharmacol157: 14–23.

Lim HD, Smits RA, Leurs R, de Esch IJ (2006). The emerging role of the histamine H4 receptor in anti-inflammatory therapy. Curr Top Med Chem6: 1365–1373.

Tanimoto A, Sasaguri Y, Ohtsu H (2006). Histamine network in atherosclerosis. Trends Cardiovasc Med16: 280–284.

Thurmond RL, Gelfand EW, Dunford PJ (2008). The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discovery7: 41–53.

Yanai K, Tashiro M (2007). The physiological and pathophysiological roles of neuronal histamine: An insight from human positron emission tomography studies. Pharmacol Ther113: 1–15.

Zampeli E, Tiligada E (2009). The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol157: 24–33.

Zhang M, Thurmond RL, Dunford PJ (2007). The histamine H₄ receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther113: 594–606.