View source for Histamine H3 receptor

{{Short description|Mammalian protein found in Homo sapiens}}
{{DISPLAYTITLE:Histamine H<sub>3</sub> receptor}}
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{{Infobox_gene}}
'''Histamine H<sub>3</sub> receptors''' are expressed in the [[central nervous system]] and to a lesser extent the [[peripheral nervous system]], where they act as [[autoreceptor]]s in presynaptic [[histamine]]rgic [[neuron]]s and control [[histamine]] turnover by feedback inhibition of histamine synthesis and release.<ref name="pmid2172771">{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–3 | date = Nov 1990 | pmid = 2172771 | url = http://molpharm.aspetjournals.org/cgi/content/abstract/38/5/610 | format = abstract }}</ref> The H<sub>3</sub> 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]], [[Gamma-aminobutyric acid|GABA]], [[acetylcholine]], [[noradrenaline]], [[histamine]] and [[serotonin]]<!-- Adding source(s) improves the quality of this interesting information. -->.

The gene sequence for H<sub>3</sub> receptors expresses only about 22% and 20% homology with both H<sub>1</sub> and H<sub>2</sub> receptors respectively.

There is much interest in the histamine H<sub>3</sub> receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive disorders and especially its location in the central nervous system.<ref name=":1">Rapanelli, Maximiliano. “The Magnificent Two: Histamine and the H3 Receptor as Key Modulators of Striatal Circuitry.” ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 73 (February 2017): 36–40</ref><ref name=":0" />

==Tissue distribution==

* [[Central nervous system]]
* [[Peripheral nervous system]]
* [[Heart]]
* [[Lung]]s
* [[Gastrointestinal tract]]
* [[Endothelial cell]]s

== Function ==
Like all histamine receptors, the H<sub>3</sub> receptor is a [[G-protein coupled receptor]]. The H<sub>3</sub> receptor is coupled to the [[Gi subunit|G<sub>i</sub>]] [[G protein|G-protein]], so it leads to inhibition of the formation of [[Cyclic adenosine monophosphate|cAMP]]. Also, the [[beta g subunit|β]] and [[gamma g subunit|γ]] subunits interact with [[N-type voltage gated calcium channels]], to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release.
H<sub>3</sub> receptors function as presynaptic [[autoreceptors]] on histamine-containing neurons.<ref name="urlInterPro: IPR003980 Histamine H3 receptor">{{cite web | url = http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980 | title = InterPro: IPR003980 Histamine H3 receptor | work = [[InterPro]] | publisher = European Bioinformatics Institute }}</ref>

The diverse expression of H<sub>3</sub> receptors throughout the [[cerebral cortex|cortex]] and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.

H<sub>3</sub> receptors are thought to play a part in the control of satiety.<ref name="pmid11459437">{{cite journal | vauthors = 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 Sciences | volume = 69 | issue = 4 | pages = 469–78 | date = Jun 2001 | pmid = 11459437 | doi = 10.1016/S0024-3205(01)01138-9 }}</ref>

==Isoforms==
There are at least six H<sub>3</sub> receptor [[isoform]]s in the human, and more than 20 discovered so far.<ref name="pmid15597144">{{cite journal | vauthors = Bakker RA | title = Histamine H3-receptor isoforms | journal = Inflammation Research | volume = 53 | issue = 10 | pages = 509–16 | date = Oct 2004 | pmid = 15597144 | doi = 10.1007/s00011-004-1286-9 | s2cid = 9630188 }}</ref> In rats six H<sub>3</sub>receptor subtypes have been identified so far. Mice also have three reported isoforms.<ref name="pmid15341517">{{cite journal | vauthors = 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 = Journal of Neurochemistry | volume = 90 | issue = 6 | pages = 1331–8 | date = Sep 2004 | pmid = 15341517 | doi = 10.1111/j.1471-4159.2004.02606.x | s2cid = 29078902 | doi-access = free }}</ref> 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.{{medical citation needed|date=March 2025}}

==Pharmacology== <!--Gβγ has a link to here-->
[[Image:Histamine.svg|thumb|[[Histamine]]]]

===Agonists===
There are currently no therapeutic products acting as selective agonists for H<sub>3</sub> receptors, although there are several compounds used as research tools which are reasonably selective agonists. Some examples are:

*[[Alpha-methylhistamine|(''R'')-α-methylhistamine]]
*[[Cipralisant]] (initially assessed as H<sub>3</sub> antagonist, later found to be an agonist, shows [[functional selectivity]], activating some G-protein coupled pathways but not others)<ref>{{cite journal | pmid = 15821027 | doi=10.1124/jpet.104.078865 | volume=314 | issue=1 | title=G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations | date=July 2005 | journal=J. Pharmacol. Exp. Ther. | pages=271–81 | vauthors=Krueger KM, Witte DG, Ireland-Denny L ''et al.''| s2cid=20470970 }}</ref>
*[[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===
{{main article|H3 receptor antagonist}}
H<sub>3</sub> receptor antagonists include:<ref name="pmid10215700">{{cite journal | vauthors = 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 = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 2 | pages = 1160–8 | date = May 1999 | pmid = 10215700 | url = http://jpet.aspetjournals.org/cgi/content/abstract/289/2/1160 | format = abstract }}</ref>
*[[A-304121]] (No tolerance formation, silent antagonist)<ref>{{cite journal | vauthors = Pan JB, Yao BB, Miller TR, Kroeger PE, Bennani YL, Komater VA, Esbenshade TA, Hancock AA, Decker MW, Fox GB | title = Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121 | journal = Life Sciences | volume = 79 | issue = 14 | pages = 1366–1379 | date = August 2006 | pmid = 16730751 | doi = 10.1016/j.lfs.2006.04.002 }}</ref>
*[[A-349,821]]<ref>{{cite journal | pmid = 15294456 | doi=10.1016/j.bcp.2004.05.048 | volume=68 | issue=5 | title=Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist | date=September 2004 | journal=Biochem. Pharmacol. | pages=933–45 | vauthors=Esbenshade TA, Fox GB, Krueger KM ''et al.''}}</ref>
*[[ABT-239]]
*[[Betahistine]] (also weak H<sub>1</sub> agonist)
*[[Burimamide]] (also weak H<sub>2</sub> antagonist)
*[[Ciproxifan]]
*[[Clobenpropit]] (also H<sub>4</sub> antagonist)
*[[Conessine]]
*[[Failproxifan]]{{Citation Needed|reason=There seems to be no evidence that "Failproxifan" exists other than this  article|date=July 2020}} (No tolerance formation){{Citation needed|date=July 2020}}
*[[Impentamine]]
*[[Iodophenpropit]]
*[[Irdabisant]]
*[[Pitolisant]]
*[[Thioperamide]] (also H<sub>4</sub> antagonist)
*[[VUF-5681]] (<nowiki>4-[3-(1H-Imidazol-4-yl)propyl]piperidine</nowiki>)

==Therapeutic potential==
The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R dysfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters.<ref name=":1" /><ref>Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” ''Neuropharmacology'' 106 (July 2016): 74–84</ref><ref name=":2">Sadek, Bassem, Ali Saad, Adel Sadeq, Fakhreya Jalal, and Holger Stark. “Histamine H3 Receptor as a Potential Target for Cognitive Symptoms in Neuropsychiatric Diseases.” ''Behavioural Brain Research'' 312 (October 2016): 415–430</ref> Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions.<ref name=":1" /><ref name=":2" />

This receptor has been proposed as a target for treating [[sleep disorder]]s.<ref>{{cite journal | vauthors = 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 in Pharmacological Sciences | volume = 25 | issue = 12 | pages = 618–25 | date = Dec 2004 | pmid = 15530639 | doi = 10.1016/j.tips.2004.10.003 }}</ref> The receptor has also been proposed as a target for treating neuropathic [[pain]].<ref>{{cite journal | vauthors = Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, Roberts JC, Medhurst AD, Chessell IP | title = Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain | journal = Pain | volume = 138 | issue = 1 | pages = 61–9 | date = Aug 2008 | pmid = 18164820 | doi = 10.1016/j.pain.2007.11.006 | s2cid = 43724064 }}</ref>

Because of its ability to modulate other neurotransmitters, H<sub>3</sub> receptor [[Ligand (biochemistry)|ligand]]s are being investigated for the treatment of numerous neurological conditions, including [[obesity]] (because of the histamine/[[orexin]]ergic system interaction), [[movement disorder]]s (because of H<sub>3</sub> receptor-modulation of dopamine and GABA in the [[basal ganglia]]), [[schizophrenia]] and [[Attention Deficit Hyperactivity Disorder|ADHD]] (again because of dopamine modulation) and research is underway to determine whether H<sub>3</sub> receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, [[glutamate]] and histamine).<ref name="pmid15665857">{{cite journal | vauthors = 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 | date = Feb 2005 | pmid = 15665857 | doi = 10.1038/nrd1631 | s2cid = 32781560 | doi-access = free }}</ref><ref name=":0">Sadek, Bassem, Ali Saad, Adel Sadeq, Fakhreya Jalal, and Holger Stark. “Histamine H3 Receptor as a Potential Target for Cognitive Symptoms in Neuropsychiatric Diseases.” ''Behavioural Brain Research'' 312 (October 2016): 415–430</ref>

There is also evidence that the H3-receptor plays an important role in [[Tourette syndrome]].<ref>Cox, Joanna H., Stefano Seri, and Andrea E. Cavanna. “Histaminergic Modulation in Tourette Syndrome.” ''Expert Opinion on Orphan Drugs'' 4, no. 2 (February 1, 2016): 205–213</ref> Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.<ref>Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” ''Neuropharmacology'' 106 (July 2016): 74–84</ref><ref>Rapanelli, Maximiliano, Luciana Frick, Haruhiko Bito, and Christopher Pittenger. “Histamine Modulation of the Basal Ganglia Circuitry in the Development of Pathological Grooming.” ''Proceedings of the National Academy of Sciences'' (June 5, 2017): 6599–6604</ref><ref>Rapanelli, Maximiliano, and Christopher Pittenger. “Histamine and Histamine Receptors in Tourette Syndrome and Other Neuropsychiatric Conditions.” ''Neuropharmacology'' 106 (July 2016): 85–90</ref> The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.<ref>Baldan, Lissandra Castellan, Kyle A. Williams, Jean-Dominique Gallezot, Vladimir Pogorelov, Maximiliano Rapanelli, Michael Crowley, George M. Anderson, et al. “Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice.” Neuron 81, no. 1 (January 8, 2014): 77–90</ref>

==History==
* 1983: The H<sub>3</sub> receptor is pharmacologically identified.<ref name="pmid6188956">{{cite journal | vauthors = 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 | date = Apr 1983 | pmid = 6188956 | doi = 10.1038/302832a0 | bibcode = 1983Natur.302..832A | s2cid = 4302564 }}</ref>
* 1988: H<sub>3</sub> receptor found to mediate inhibition of serotonin release in rat brain cortex.<ref name="pmid3412497">{{cite journal | vauthors = Schlicker E, Betz R, Göthert M | title = Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 337 | issue = 5 | pages = 588–90 | date = May 1988 | pmid = 3412497 | doi = 10.1007/BF00182737 | s2cid = 24168192 }}</ref>
* 1997: H<sub>3</sub> receptors shown to modulate [[ischemia|ischemic]] [[norepinephrine]] release in animals.<ref name="pmid9353362">{{cite journal | vauthors = 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 = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 2 | pages = 494–500 | date = Nov 1997 | pmid = 9353362 | url = http://jpet.aspetjournals.org/cgi/content/abstract/283/2/494 | format = abstract }}</ref>
* 1999: H<sub>3</sub> receptor cloned<ref name="pmid10347254">{{cite journal | vauthors = 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 = Molecular Pharmacology | volume = 55 | issue = 6 | pages = 1101–7 | date = Jun 1999 | pmid = 10347254 | doi =  10.1124/mol.55.6.1101| s2cid = 25542667 }}</ref>
* 2000: H<sub>3</sub> receptors called "new frontier in [[myocardial ischemia]]"<ref name="pmid10688593">{{cite journal | vauthors = Levi R, Smith NC | title = Histamine H(3)-receptors: a new frontier in myocardial ischemia | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 3 | pages = 825–30 | date = Mar 2000 | pmid = 10688593 | url = http://jpet.aspetjournals.org/cgi/content/abstract/292/3/825 | format = abstract }}</ref>
* 2002: H<sub>3</sub><sup>(-/-)</sup> mice (mice that do not have this receptor)<ref name="pmid12130692">{{cite journal | vauthors = 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 H(3) receptors | journal = Molecular Pharmacology | volume = 62 | issue = 2 | pages = 389–97 | date = Aug 2002 | pmid = 12130692 | doi = 10.1124/mol.62.2.389 | s2cid = 25583387 }}</ref>


== See also ==
* [[Antihistamine]] – histamine receptor antagonists
* [[H3_receptor_antagonist|H<sub>3</sub>-receptor antagonist]]
* [[Histamine H1 receptor|Histamine H<sub>1</sub>-receptor]]
* [[Histamine H2 receptor|Histamine H<sub>2</sub>-receptor]]
* [[Histamine H4 receptor|Histamine H<sub>4</sub>-receptor]]

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL | title = International Union of Pharmacology. XIII. Classification of histamine receptors | journal = Pharmacological Reviews | volume = 49 | issue = 3 | pages = 253–78 | date = Sep 1997 | pmid = 9311023 }}
* {{cite journal | vauthors = Malinowska B, Godlewski G, Schlicker E | title = Histamine H3 receptors--general characterization and their function in the cardiovascular system | journal = Journal of Physiology and Pharmacology | volume = 49 | issue = 2 | pages = 191–211 | date = Jun 1998 | pmid = 9670104 }}
* {{cite journal | vauthors = Leurs R, Hoffmann M, Wieland K, Timmerman H | title = H3 receptor gene is cloned at last | journal = Trends in Pharmacological Sciences | volume = 21 | issue = 1 | pages = 11–2 | date = Jan 2000 | pmid = 10637648 | doi = 10.1016/S0165-6147(99)01411-X }}
* {{cite journal | vauthors = 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 | date = Feb 2005 | pmid = 15665857 | doi = 10.1038/nrd1631 | s2cid = 32781560 | doi-access = free }}
* {{cite journal | vauthors = Esbenshade TA, Fox GB, Cowart MD | title = Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders | journal = Molecular Interventions | volume = 6 | issue = 2 | pages = 77–88, 59 | date = Apr 2006 | pmid = 16565470 | doi = 10.1124/mi.6.2.5 }}
* {{cite journal | vauthors = 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 = Molecular Pharmacology | volume = 55 | issue = 6 | pages = 1101–7 | date = Jun 1999 | pmid = 10347254 | doi =  10.1124/mol.55.6.1101| s2cid = 25542667 }}
* {{cite journal | vauthors = Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K | title = Molecular cloning and characterization of a new human histamine receptor, HH4R | journal = Biochemical and Biophysical Research Communications | volume = 279 | issue = 2 | pages = 615–20 | date = Dec 2000 | pmid = 11118334 | doi = 10.1006/bbrc.2000.4008 }}
* {{cite journal | vauthors = Cogé F, Guénin SP, Audinot V, Renouard-Try A, Beauverger P, Macia C, Ouvry C, Nagel N, Rique H, Boutin JA, Galizzi JP | title = Genomic organization and characterization of splice variants of the human histamine H3 receptor | journal = The Biochemical Journal | volume = 355 | issue = Pt 2 | pages = 279–88 | date = Apr 2001 | pmid = 11284713 | pmc = 1221737 | doi = 10.1042/0264-6021:3550279 }}
* {{cite journal | vauthors = Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R | title = Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 1 | pages = 501–6 | date = Jan 2002 | pmid = 11752397 | pmc = 117589 | doi = 10.1073/pnas.012506099 | bibcode = 2002PNAS...99..501S | doi-access = free }}
* {{cite journal | vauthors = 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 | volume = 109 | issue = 4 | pages = 443–53 | date = Apr 2002 | pmid = 11956964 | doi = 10.1007/s007020200036 | s2cid = 32434148 }}
* {{cite journal | vauthors = Wellendorph P, Goodman MW, Burstein ES, Nash NR, Brann MR, Weiner DM | 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 | date = Jun 2002 | pmid = 12069903 | doi = 10.1016/S0028-3908(02)00041-2 | s2cid = 54326678 }}
* {{cite journal | vauthors = 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 = Journal of Hepatology | volume = 39 | issue = 4 | pages = 522–7 | date = Oct 2003 | pmid = 12971961 | doi = 10.1016/S0168-8278(03)00353-2 | url = http://www.journal-of-hepatology.eu/article/S0168827803003532/pdf | url-access = subscription }}
* {{cite journal | vauthors = 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 | title = Human skin mast cells express H2 and H4, but not H3 receptors | journal = The Journal of Investigative Dermatology | volume = 123 | issue = 1 | pages = 116–23 | date = Jul 2004 | pmid = 15191551 | doi = 10.1111/j.0022-202X.2004.22721.x | doi-access = free }}
{{refend}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307 | title = Histamine Receptors: H<sub>3</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2006-07-20 | archive-date = 2013-12-25 | archive-url = https://web.archive.org/web/20131225114708/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307 | url-status = dead }}
*{{MeshName|H3+receptors}}

{{G protein-coupled receptors}}
{{Histaminergics}}

[[Category:Histamine receptors]]