Histamine H3 receptor

HRH3
Identifiers
Aliases HRH3, GPCR97, HH3R, histamine receptor H3
External IDs MGI: 2139279 HomoloGene: 5232 GeneCards: HRH3
Targeted by Drug
dimaprit, histamine, imetit, Immepip, Immethridine, Impentamine, methimepip, proxyfan, mk-0249, impromidine, ciproxifan, clobenpropit, conessine, jnj-5207852, pitolisant, thioperamide, abt-239[1]
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_009163.2

NP_598610.1

Location (UCSC) Chr 20: 62.21 – 62.22 Mb Chr 2: 180.1 – 180.1 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

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.[4] 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

Function

Like all histamine receptors the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi 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.[5]

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.[6]

Isoforms

There are at least six H3 receptor isoforms in the human, and more than 20 discovered so far.[7] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.[8] 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:

Antagonists

These include:[10]

Therapeutic potential

This receptor has been proposed as a target for treating sleep disorders.[12] The receptor has also been proposed as a target for treating neuropathic pain.[13]

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).[14]

History

See also

References

  1. ↑ "Drugs that physically interact with Histamine H3 receptor view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ 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.
  5. ↑ "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute.
  6. ↑ 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.
  7. ↑ Bakker RA (Oct 2004). "Histamine H3-receptor isoforms". Inflammation Research. 53 (10): 509–16. doi:10.1007/s00011-004-1286-9. PMID 15597144.
  8. ↑ 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.
  9. ↑ 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
  10. ↑ 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.
  11. ↑ 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
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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 1221737Freely accessible. 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 117589Freely accessible. 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

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