Histamine H3 receptor

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.cite journal | author = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Mol. Pharmacol. | volume = 38 | issue = 5 | pages = 610–3 | year = 1990 | pmid = 2172771 | doi = | issn = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/38/5/610 | format = abstract ] 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, 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


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.cite web | url = http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980 | title = InterPro: IPR003980 Histamine H3 receptor | author = | authorlink = | coauthors = | date = | format = | work = InterPro | publisher = European Bioinformatics Institute | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = ]

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.cite journal | author = Attoub S, Moizo L, Sobhani I, Laigneau JP, Lewin MJ, Bado A | title = The H3 receptor is involved in cholecystokinin inhibition of food intake in rats | journal = Life Sci. | volume = 69 | issue = 4 | pages = 469–78 | year = 2001 | month = June | pmid = 11459437 | doi = 10.1016/S0024-3205(01)01138-9 | url = | issn = ]


There are at least six H3 receptor isoforms in the human, and up to 12 discovered so far.cite journal | author = Bakker RA | title = Histamine H3-receptor isoforms | journal = Inflamm. Res. | volume = 53 | issue = 10 | pages = 509–16 | year = 2004 | pmid = 15597144 | doi = 10.1007/s00011-004-1286-9 ] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.cite journal | author = Rouleau A, Héron A, Cochois V, Pillot C, Schwartz JC, Arrang JM | title = Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms | journal = J. Neurochem. | volume = 90 | issue = 6 | pages = 1331–8 | year = 2004 | pmid = 15341517 | doi = 10.1111/j.1471-4159.2004.02606.x ] 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.



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:

*Cipralisant (initially assessed as H3 antagonist, later found to be an agonist, shows functional selectivity, activating some G-protein coupled pathways but not others) [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]
*Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release)


These include:cite journal | author = Tedford CE, Phillips JG, Gregory R, Pawlowski GP, Fadnis L, Khan MA, Ali SM, Handley MK, Yates SL | title = Development of trans-2-(1H-imidazol-4-yl) cyclopropane derivatives as new high-affinity histamine H3 receptor ligands | journal = J. Pharmacol. Exp. Ther. | volume = 289 | issue = 2 | pages = 1160–8 | year = 1999 | pmid = 10215700 | doi = | issn = | url = http://jpet.aspetjournals.org/cgi/content/abstract/289/2/1160 | format = abstract ]
*A-349,821 [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 Sep 1;68(5):933-45. PMID 15294456]
*Burimamide (also weak H2 antagonist)
*Clobenpropit (also H4 antagonist)
*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. [cite journal|author=Passani MB, Lin JS, Hancock A, Crochet S, Blandina P |title=The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders |journal=Trends Pharmacol. Sci. |volume=25 |issue=12 |pages=618–25 |year=2004 |pmid=15530639 |doi=10.1016/j.tips.2004.10.003]

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).cite journal | author = Leurs R, Bakker RA, Timmerman H, de Esch IJ | title = The histamine H3 receptor: from gene cloning to H3 receptor drugs | journal = Nature reviews. Drug discovery | volume = 4 | issue = 2 | pages = 107–20 | year = 2005 | pmid = 15665857 | doi = 10.1038/nrd1631 ]


* 1983 The H3 receptor is pharmacologically identified.cite journal | author = Arrang JM, Garbarg M, Schwartz JC | title = Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor | journal = Nature | volume = 302 | issue = 5911 | pages = 832–7 | year = 1983 | pmid = 6188956 | doi = 10.1038/302832a0 ]
* 1988 H3 receptor found to mediate inhibition of serotonin release in rat brain cortex.cite journal | author = Schlicker E, Betz R, Göthert M | title = Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex | journal = Naunyn Schmiedebergs Arch. Pharmacol. | volume = 337 | issue = 5 | pages = 588–90 | year = 1988 | pmid = 3412497 | doi = 10.1007/BF00182737 ]
* 1997 H3 receptors shown to modulate ischemic norepinephrine release in animals.cite journal | author = Hatta E, Yasuda K, Levi R | title = Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia | journal = J. Pharmacol. Exp. Ther. | volume = 283 | issue = 2 | pages = 494–500 | year = 1997 | pmid = 9353362 | doi = | issn = | url = http://jpet.aspetjournals.org/cgi/content/abstract/283/2/494 | format = abstract ]
* 1999 H3 receptor clonedcite journal | author = Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG | title = Cloning and functional expression of the human histamine H3 receptor | journal = Mol. Pharmacol. | volume = 55 | issue = 6 | pages = 1101–7 | year = 1999 | pmid = 10347254 | doi = | issn = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/55/6/1101 | format = abstract]
* 2000 H3 receptors called "new frontier in myocardial ischemia"cite journal | author = Levi R, Smith NC | title = Histamine H3-receptors: a new frontier in myocardial ischemia | journal = J. Pharmacol. Exp. Ther. | volume = 292 | issue = 3 | pages = 825–30 | year = 2000 | pmid = 10688593 | doi = | issn = | url = http://jpet.aspetjournals.org/cgi/content/abstract/292/3/825 | format = abstract ]
* 2002 H3(-/-) mice (mice that do not have this receptor)cite journal | author = 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 | title = Behavioral characterization of mice lacking histamine H3 receptors | journal = Mol. Pharmacol. | volume = 62 | issue = 2 | pages = 389–97 | year = 2002 | pmid = 12130692 | doi = 10.1124/mol.62.2.389 ]

See also

* Histamine_antagonist#H3-receptor_antagonists


Further reading

citations =
*cite journal | author=Hill SJ, Ganellin CR, Timmerman H, "et al." |title=International Union of Pharmacology. XIII. Classification of histamine receptors |journal=Pharmacol. Rev. |volume=49 |issue= 3 |pages= 253–78 |year= 1997 |pmid= 9311023 |doi=
*cite journal | author=Malinowska B, Godlewski G, Schlicker E |title=Histamine H3 receptors--general characterization and their function in the cardiovascular system |journal=J. Physiol. Pharmacol. |volume=49 |issue= 2 |pages= 191–211 |year= 1998 |pmid= 9670104 |doi=
*cite journal | author=Leurs R, Hoffmann M, Wieland K, Timmerman H |title=H3 receptor gene is cloned at last |journal=Trends Pharmacol. Sci. |volume=21 |issue= 1 |pages= 11–2 |year= 2000 |pmid= 10637648 |doi=
*cite journal | author=Leurs R, Bakker RA, Timmerman H, de Esch IJ |title=The histamine H3 receptor: from gene cloning to H3 receptor drugs |journal=Nature reviews. Drug discovery |volume=4 |issue= 2 |pages= 107–20 |year= 2005 |pmid= 15665857 |doi= 10.1038/nrd1631
*cite journal | author=Esbenshade TA, Fox GB, Cowart MD |title=Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders |journal=Mol. Interv. |volume=6 |issue= 2 |pages= 77–88, 59 |year= 2006 |pmid= 16565470 |doi= 10.1124/mi.6.2.5
*cite journal | author=Lovenberg TW, Roland BL, Wilson SJ, "et al." |title=Cloning and functional expression of the human histamine H3 receptor |journal=Mol. Pharmacol. |volume=55 |issue= 6 |pages= 1101–7 |year= 1999 |pmid= 10347254 |doi=
*cite journal | author=Nakamura T, Itadani H, Hidaka Y, "et al." |title=Molecular cloning and characterization of a new human histamine receptor, HH4R |journal=Biochem. Biophys. Res. Commun. |volume=279 |issue= 2 |pages= 615–20 |year= 2001 |pmid= 11118334 |doi= 10.1006/bbrc.2000.4008
*cite journal | author=Cogé F, Guénin SP, Audinot V, "et al." |title=Genomic organization and characterization of splice variants of the human histamine H3 receptor |journal=Biochem. J. |volume=355 |issue= Pt 2 |pages= 279–88 |year= 2001 |pmid= 11284713 |doi=
*cite journal | author=Silver RB, Poonwasi KS, Seyedi N, "et al." |title=Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 1 |pages= 501–6 |year= 2002 |pmid= 11752397 |doi= 10.1073/pnas.012506099
*cite journal | author=Deloukas P, Matthews LH, Ashurst J, "et al." |title=The DNA sequence and comparative analysis of human chromosome 20 |journal=Nature |volume=414 |issue= 6866 |pages= 865–71 |year= 2002 |pmid= 11780052 |doi= 10.1038/414865a
*cite journal | author=Wiedemann P, Bönisch H, Oerters F, Brüss M |title=Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations |journal=Journal of neural transmission (Vienna, Austria : 1996) |volume=109 |issue= 4 |pages= 443–53 |year= 2002 |pmid= 11956964 |doi= 10.1007/s007020200036
*cite journal | author=Wellendorph P, Goodman MW, Burstein ES, "et al." |title=Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor |journal=Neuropharmacology |volume=42 |issue= 7 |pages= 929–40 |year= 2002 |pmid= 12069903 |doi=
*cite journal | author=Strausberg RL, Feingold EA, Grouse LH, "et al." |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899
*cite journal | author=Lozeva V, Tuomisto L, Tarhanen J, Butterworth RF |title=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=J. Hepatol. |volume=39 |issue= 4 |pages= 522–7 |year= 2004 |pmid= 12971961 |doi=
*cite journal | author=Lippert U, Artuc M, Grützkau A, "et al." |title=Human skin mast cells express H2 and H4, but not H3 receptors |journal=J. Invest. Dermatol. |volume=123 |issue= 1 |pages= 116–23 |year= 2004 |pmid= 15191551 |doi= 10.1111/j.0022-202X.2004.22721.x
*cite journal | author=Gerhard DS, Wagner L, Feingold EA, "et al." |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504

External links

* [http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307 IUPHAR GPCR Database - H3 Histamine Receptor]

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