Histamine H3 receptor

Histamine receptor H3
Identifiers
Symbols	HRH3 ; GPCR97; HH3R
External IDs	OMIM: 604525 MGI: 2139279 HomoloGene: 5232 IUPHAR: 264 ChEMBL: 264 GeneCards: HRH3 Gene
Gene ontology Molecular function • histamine receptor activity • histamine binding Cellular component • plasma membrane • integral component of plasma membrane Biological process • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • negative regulation of adenylate cyclase activity • neurotransmitter secretion • sensory perception of chemical stimulus • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • negative regulation of glutamate secretion • regulation of norepinephrine secretion • negative regulation of serotonin secretion • cognition Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	11255	99296
Ensembl	ENSG00000101180	ENSMUSG00000039059
UniProt	Q9Y5N1	P58406
RefSeq (mRNA)	NM_007232	NM_133849
RefSeq (protein)	NP_009163	NP_598610
Location (UCSC)	Chr 20: 62.21 – 62.22 Mb	Chr 2: 180.1 – 180.1 Mb
PubMed search

Histamine H₃ receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release.^[1] The H₃ receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.

The gene sequence for H₃ receptors expresses only about 22% and 20% homology with both H₁ and H₂ receptors respectively.

Tissue distribution

• Central nervous system
• Peripheral nervous system
• Heart
• Lungs
• Gastrointestinal tract
• Endothelial cells

Function

Like all histamine receptors the H₃ receptor is a G-protein coupled receptor. The H₃ receptor is coupled to the G_i G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H₃ receptors function as presynaptic autoreceptors on histamine-containing neurons.^[2]

The diverse expression of H₃ receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.

H₃ receptors are thought to play a part in the control of satiety.^[3]

Isoforms

There are at least six H₃ receptor isoforms in the human, and more than 20 discovered so far.^[4] In rats there have been six H₃receptor subtypes identified so far. Mice also have three reported isoforms.^[5] These subtypes all have subtle difference in their pharmacology (and presumably distribution, based on studies in rats) but the exact physiological role of these isoforms is still unclear.

Pharmacology

Histamine

Agonists

There are currently no therapeutic products acting as selective agonists for H₃ receptors, although there are several compounds used as research tools which are reasonably selective agonists. Some examples are:

• (R)-α-methylhistamine
• Cipralisant (initially assessed as H₃ antagonist, later found to be an agonist, shows functional selectivity, activating some G-protein coupled pathways but not others)^[6]
• Imbutamine (also H4 agonist)
• Immepip
• Imetit
• Immethridine
• Methimepip
• Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release)

Antagonists

These include:^[7]

• A-349,821^[8]
• ABT-239
• Betahistine (also weak H₁ agonist)
• Burimamide (also weak H₂ antagonist)
• Ciproxifan
• Clobenpropit (also H₄ antagonist)
• Conessine
• Failproxifan (no tolerance formation, like with Ciproxifan)
• Impentamine
• Iodophenpropit
• Irdabisant
• Pitolisant
• Thioperamide (also H₄ antagonist)
• VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)

Therapeutic potential

This receptor has been proposed as a target for treating sleep disorders.^[9] The receptor has also been proposed as a target for treating neuropathic pain.^[10]

Because of its ability to modulate other neurotransmitters, H₃ receptor ligands are being investigated for the treatment of numerous neurological conditions, including obesity (because of the histamine/orexinergic system interaction), movement disorders (because of H₃ receptor-modulation of dopamine and GABA in the basal ganglia), schizophrenia and ADHD (again because of dopamine modulation) and research is underway to determine whether H₃ receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine).^[11]

History

• 1983 The H₃ receptor is pharmacologically identified.^[12]
• 1988 H₃ receptor found to mediate inhibition of serotonin release in rat brain cortex.^[13]
• 1997 H₃ receptors shown to modulate ischemic norepinephrine release in animals.^[14]
• 1999 H₃ receptor cloned^[15]
• 2000 H₃ receptors called "new frontier in myocardial ischemia"^[16]
• 2002 H₃^(-/-) mice (mice that do not have this receptor)^[17]

See also

• Histamine_antagonist#H3-receptor_antagonists

References

1. West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA (Nov 1990). "Identification of two H3-histamine receptor subtypes" (abstract). Molecular Pharmacology 38 (5): 610–3. PMID 2172771.
2. "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute.
3. Attoub S, Moizo L, Sobhani I, Laigneau JP, Lewin MJ, Bado A (Jun 2001). "The H3 receptor is involved in cholecystokinin inhibition of food intake in rats". Life Sciences 69 (4): 469–78. doi:10.1016/S0024-3205(01)01138-9. PMID 11459437.
4. Bakker RA (Oct 2004). "Histamine H3-receptor isoforms". Inflammation Research 53 (10): 509–16. doi:10.1007/s00011-004-1286-9. PMID 15597144.
5. Rouleau A, Héron A, Cochois V, Pillot C, Schwartz JC, Arrang JM (Sep 2004). "Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms". Journal of Neurochemistry 90 (6): 1331–8. doi:10.1111/j.1471-4159.2004.02606.x. PMID 15341517.
6. Krueger KM, Witte DG, Ireland-Denny L, Miller TR, Baranowski JL, Buckner S, Milicic I, Esbenshade TA, Hancock AA. G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations. Journal of Pharmacology and Experimental Therapeutics. 2005 Jul;314(1):271-81. PMID 15821027
7. Tedford CE, Phillips JG, Gregory R, Pawlowski GP, Fadnis L, Khan MA, Ali SM, Handley MK, Yates SL (May 1999). "Development of trans-2-[1H-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H3 receptor ligands" (abstract). The Journal of Pharmacology and Experimental Therapeutics 289 (2): 1160–8. PMID 10215700.
8. Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan JB, Faghih R, Bennani YL, Williams M, Hancock AA. Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist. Biochemical Pharmacology. 2004 September 1;68(5):933-45. PMID 15294456
9. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P (Dec 2004). "The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders". Trends in Pharmacological Sciences 25 (12): 618–25. doi:10.1016/j.tips.2004.10.003. PMID 15530639.
10. Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, Roberts JC, Medhurst AD, Chessell IP (Aug 2008). "Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain". Pain 138 (1): 61–9. doi:10.1016/j.pain.2007.11.006. PMID 18164820.
11. Leurs R, Bakker RA, Timmerman H, de Esch IJ (Feb 2005). "The histamine H3 receptor: from gene cloning to H3 receptor drugs". Nature Reviews. Drug Discovery 4 (2): 107–20. doi:10.1038/nrd1631. PMID 15665857.
12. Arrang JM, Garbarg M, Schwartz JC (Apr 1983). "Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor". Nature 302 (5911): 832–7. doi:10.1038/302832a0. PMID 6188956.
13. Schlicker E, Betz R, Göthert M (May 1988). "Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex". Naunyn-Schmiedeberg's Archives of Pharmacology 337 (5): 588–90. doi:10.1007/BF00182737. PMID 3412497.
14. Hatta E, Yasuda K, Levi R (Nov 1997). "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia" (abstract). The Journal of Pharmacology and Experimental Therapeutics 283 (2): 494–500. PMID 9353362.
15. Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG (Jun 1999). "Cloning and functional expression of the human histamine H3 receptor" (abstract). Molecular Pharmacology 55 (6): 1101–7. PMID 10347254.
16. Levi R, Smith NC (Mar 2000). "Histamine H(3)-receptors: a new frontier in myocardial ischemia" (abstract). The Journal of Pharmacology and Experimental Therapeutics 292 (3): 825–30. PMID 10688593.
17. Toyota H, Dugovic C, Koehl M, Laposky AD, Weber C, Ngo K, Wu Y, Lee DH, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier AJ, Turek FW, Fung-Leung WP, Lovenberg TW (Aug 2002). "Behavioral characterization of mice lacking histamine H(3) receptors". Molecular Pharmacology 62 (2): 389–97. doi:10.1124/mol.62.2.389. PMID 12130692.

Further reading

• Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL (Sep 1997). "International Union of Pharmacology. XIII. Classification of histamine receptors". Pharmacological Reviews 49 (3): 253–78. PMID 9311023.
• Malinowska B, Godlewski G, Schlicker E (Jun 1998). "Histamine H3 receptors--general characterization and their function in the cardiovascular system". Journal of Physiology and Pharmacology 49 (2): 191–211. PMID 9670104.
• Leurs R, Hoffmann M, Wieland K, Timmerman H (Jan 2000). "H3 receptor gene is cloned at last". Trends in Pharmacological Sciences 21 (1): 11–2. doi:10.1016/S0165-6147(99)01411-X. PMID 10637648.
• Leurs R, Bakker RA, Timmerman H, de Esch IJ (Feb 2005). "The histamine H3 receptor: from gene cloning to H3 receptor drugs". Nature Reviews. Drug Discovery 4 (2): 107–20. doi:10.1038/nrd1631. PMID 15665857.
• Esbenshade TA, Fox GB, Cowart MD (Apr 2006). "Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders". Molecular Interventions 6 (2): 77–88, 59. doi:10.1124/mi.6.2.5. PMID 16565470.
• Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG (Jun 1999). "Cloning and functional expression of the human histamine H3 receptor". Molecular Pharmacology 55 (6): 1101–7. PMID 10347254.
• Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K (Dec 2000). "Molecular cloning and characterization of a new human histamine receptor, HH4R". Biochemical and Biophysical Research Communications 279 (2): 615–20. doi:10.1006/bbrc.2000.4008. PMID 11118334.
• Cogé F, Guénin SP, Audinot V, Renouard-Try A, Beauverger P, Macia C, Ouvry C, Nagel N, Rique H, Boutin JA, Galizzi JP (Apr 2001). "Genomic organization and characterization of splice variants of the human histamine H3 receptor". The Biochemical Journal 355 (Pt 2): 279–88. doi:10.1042/0264-6021:3550279. PMC 1221737. PMID 11284713.
• Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R (Jan 2002). "Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings". Proceedings of the National Academy of Sciences of the United States of America 99 (1): 501–6. doi:10.1073/pnas.012506099. PMC 117589. PMID 11752397.
• Wiedemann P, Bönisch H, Oerters F, Brüss M (Apr 2002). "Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations". Journal of Neural Transmission 109 (4): 443–53. doi:10.1007/s007020200036. PMID 11956964.
• Wellendorph P, Goodman MW, Burstein ES, Nash NR, Brann MR, Weiner DM (Jun 2002). "Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor". Neuropharmacology 42 (7): 929–40. doi:10.1016/S0028-3908(02)00041-2. PMID 12069903.
• Lozeva V, Tuomisto L, Tarhanen J, Butterworth RF (Oct 2003). "Increased concentrations of histamine and its metabolite, tele-methylhistamine and down-regulation of histamine H3 receptor sites in autopsied brain tissue from cirrhotic patients who died in hepatic coma". Journal of Hepatology 39 (4): 522–7. doi:10.1016/S0168-8278(03)00353-2. PMID 12971961.
• Lippert U, Artuc M, Grützkau A, Babina M, Guhl S, Haase I, Blaschke V, Zachmann K, Knosalla M, Middel P, Krüger-Krasagakis S, Henz BM (Jul 2004). "Human skin mast cells express H2 and H4, but not H3 receptors". The Journal of Investigative Dermatology 123 (1): 116–23. doi:10.1111/j.0022-202X.2004.22721.x. PMID 15191551.

External links

• "Histamine Receptors: H₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• H3 receptors at the US National Library of Medicine Medical Subject Headings (MeSH)