Histamine H3 receptor
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2008-07-08T01:16:56Z
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{{Wrongtitle|title=Histamine H<sub>3</sub> receptor}}
{{PBB|geneid=11255}}
'''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|histaminergic]] [[neuron]]s, and control [[histamine]] turnover<ref>[http://www.bioportfolio.com/LeadDiscovery/PubMed-120407.html Abbott's H<sub>3</sub> histamine receptor antagonist, ABT-239, a candidate treatment of cognitive disorders, ADHD, Alzheimer's and schizophrenia]</ref> by feedback inhibition of histamine synthesis and release as well.<ref name="pmid2172771">{{cite journal | author = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H<sub>3</sub>-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 }}</ref> The H<sub>3</sub> receptor 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]], and [[serotonin]].
This receptor has been proposed as a target for treating [[sleep disorder]]s.<ref>{{cite journal |author=Passani MB, Lin JS, Hancock A, Crochet S, Blandina P |title=The histamine H<sub>3</sub> 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}}</ref>
==Locations of H<sub>3</sub> receptors==
* [[Central nervous system]]
* Peripheral nerves
* [[Heart]]
* [[Lung]]s
* [[Gastrointestinal tract]]
* [[Endothelial cell]]s
==Function==
H3 receptors function as presynaptic [[autoreceptors]] on histamine-containing neurons <ref> [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980 InterPro: IPR003980 Histamine H3 receptor]</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.
H3 receptors are thought to play a part in the control of satiety.
==Pharmacology== <!--Gβγ has a link to here-->
[[Image:Histamine.png|thumb|[[Histamine]]]]
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.
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'''.
===Pharmacologic potential===
Because of its ability to modulate other neurotransmitters, H<sub>3</sub> receptor [[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 even underway as to 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 | author = Leurs R, Bakker RA, Timmerman H, de Esch IJ | title = The histamine H<sub>3</sub> 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 | issn = }}</ref>
==Isoforms==
There are at least six H<sub>3</sub> receptor [[isoform]]s in the human, and up to 12 discovered so far.<ref name="pmid15597144">{{cite journal | author = Bakker RA | title = Histamine H<sub>3</sub>-receptor isoforms | journal = Inflamm. Res. | volume = 53 | issue = 10 | pages = 509–16 | year = 2004 | pmid = 15597144 | doi = 10.1007/s00011-004-1286-9 | issn = }}</ref> In rats there have been six H<sub>3</sub> receptor subtypes identified so far. Mice also have three reported isoforms.<ref name="pmid15341517">{{cite journal | author = Rouleau A, Héron A, Cochois V, Pillot C, Schwartz JC, Arrang JM | title = Cloning and expression of the mouse histamine H<sub>3</sub> 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 | issn = }}</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.
==History==
* [[1983]] The H<sub>3</sub> receptor is pharmacologically identified.<ref name="pmid6188956">{{cite journal | author = Arrang JM, Garbarg M, Schwartz JC | title = Auto-inhibition of brain histamine release mediated by a novel class (H<sub>3</sub>) of histamine receptor | journal = Nature | volume = 302 | issue = 5911 | pages = 832–7 | year = 1983 | pmid = 6188956 | doi = 10.1038/302832a0 | issn = }}</ref>
* [[1988]] H<sub>3</sub> receptor found to mediate inhibition of serotonin release in rat brain cortex.<ref name="pmid3412497">{{cite journal | author = Schlicker E, Betz R, Göthert M | title = Histamine H<sub>3</sub> 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 | issn = }}</ref>
* [[1997]] H<sub>3</sub> receptors shown to modulate [[ischemia|ischemic]] [[norepinephrine]] release in animals.<ref name="pmid9353362">{{cite journal | author = Hatta E, Yasuda K, Levi R | title = Activation of histamine H<sub>3</sub> 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 }}</ref>
* [[1999]] H<sub>3</sub> receptor cloned<ref name="pmid10347254">{{cite 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 H<sub>3</sub> 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}}</ref>
* [[2000]] H<sub>3</sub> receptors called "new frontier in [[myocardial ischemia]]"<ref name="pmid10688593">{{cite journal | author = Levi R, Smith NC | title = Histamine H<sub>3</sub>-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 }}</ref>
* [[2002]] H<sub>3</sub><sup>(-/-)</sup> mice (mice that do not have this receptor)<ref name="pmid12130692">{{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 H<sub>3</sub> receptors | journal = Mol. Pharmacol. | volume = 62 | issue = 2 | pages = 389–97 | year = 2002 | pmid = 12130692 | doi = 10.1124/mol.62.2.389 | issn = }}</ref>
==H<sub>3</sub> receptors agonists and antagonists==
===H<sub>3</sub>-receptor Agonists===
Currently no therapeutic products selective for H<sub>3</sub> receptors. Some, though not totally selective, are:
*[[R-α-methylhistamine]]
*[[Immepip]]
**Addition of methy groups to the α and β [[side chain]] of histamine can result in potent H<sub>3</sub>-receptor agonists.
===H<sub>3</sub>-receptor Antagonists===
These include:<ref name="pmid10215700">{{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 H<sub>3</sub> 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 }}</ref>
*[[ABT-239]]
*[[GT-2331]]
*[[Thioperamide]]
*[[Clobenpropit]]
See also [[Histamine_antagonist#H3-receptor_antagonists]].
==References==
{{Reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_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 }}
}}
{{refend}}
==External links==
*[http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307 IUPHAR GPCR Database - H<sub>3</sub> Histamine Receptor]
*{{MeshName|H3+receptors}}
{{G protein-coupled receptors}}
[[Category:G protein coupled receptors]]
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