| Histamine receptor H3 |
| Identifiers |
| Symbols |
HRH3; GPCR97; HH3R |
| External IDs |
OMIM: 604525 MGI: 2139279 HomoloGene: 5232 IUPHAR: H3 ChEMBL: 264 GeneCards: HRH3 Gene |
| Gene Ontology |
| Molecular function |
• histamine receptor activity
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| Cellular component |
• plasma membrane
• integral to plasma membrane
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| Biological process |
• G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
• neurotransmitter secretion
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| Sources: Amigo / QuickGO |
|
| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
11255 |
99296 |
|
| Ensembl |
ENSG00000101180 |
ENSMUSG00000039059 |
|
| UniProt |
Q9Y5N1 |
P58406 |
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| RefSeq (mRNA) |
NM_007232.2 |
NM_133849.2 |
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| RefSeq (protein) |
NP_009163.2 |
NP_598610.1 |
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| Location (UCSC) |
Chr 20:
60.79 – 60.8 Mb |
Chr 2:
180.1 – 180.1 Mb |
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| PubMed search |
[1] |
[2] |
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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, and serotonin.
The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.
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Contents
- 1 Tissue distribution
- 2 Function
- 3 Isoforms
- 4 Pharmacology
- 4.1 Agonists
- 4.2 Antagonists
- 5 Therapeutic potential
- 6 History
- 7 See also
- 8 References
- 9 Further reading
- 10 External links
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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 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.[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
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]
- 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
- Conessine
- Clobenpropit (also H4 antagonist)
- Impentamine
- Iodophenpropit
- 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
- ^ West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA (1990). "Identification of two H3-histamine receptor subtypes" (abstract). Mol. Pharmacol. 38 (5): 610–3. PMID 2172771. http://molpharm.aspetjournals.org/cgi/content/abstract/38/5/610.
- ^ "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute. http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980.
- ^ Attoub S, Moizo L, Sobhani I, Laigneau JP, Lewin MJ, Bado A (June 2001). "The H3 receptor is involved in cholecystokinin inhibition of food intake in rats". Life Sci. 69 (4): 469–78. doi:10.1016/S0024-3205(01)01138-9. PMID 11459437.
- ^ Bakker RA (2004). "Histamine H3-receptor isoforms". Inflamm. Res. 53 (10): 509–16. doi:10.1007/s00011-004-1286-9. PMID 15597144.
- ^ Rouleau A, Héron A, Cochois V, Pillot C, Schwartz JC, Arrang JM (2004). "Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms". J. Neurochem. 90 (6): 1331–8. doi:10.1111/j.1471-4159.2004.02606.x. PMID 15341517.
- ^ 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
- ^ Tedford CE, Phillips JG, Gregory R, Pawlowski GP, Fadnis L, Khan MA, Ali SM, Handley MK, Yates SL (1999). "Development of trans-2-(1H-imidazol-4-yl) cyclopropane derivatives as new high-affinity histamine H3 receptor ligands" (abstract). J. Pharmacol. Exp. Ther. 289 (2): 1160–8. PMID 10215700. http://jpet.aspetjournals.org/cgi/content/abstract/289/2/1160.
- ^ 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
- ^ Passani MB, Lin JS, Hancock A, Crochet S, Blandina P (2004). "The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders". Trends Pharmacol. Sci. 25 (12): 618–25. doi:10.1016/j.tips.2004.10.003. PMID 15530639.
- ^ Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, Roberts JC, Medhurst AD, Chessell IP (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): 61–78. doi:10.1016/j.pain.2007.11.006. PMID 18164820.
- ^ Leurs R, Bakker RA, Timmerman H, de Esch IJ (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.
- ^ Arrang JM, Garbarg M, Schwartz JC (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.
- ^ Schlicker E, Betz R, Göthert M (1988). "Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex". Naunyn Schmiedebergs Arch. Pharmacol. 337 (5): 588–90. doi:10.1007/BF00182737. PMID 3412497.
- ^ Hatta E, Yasuda K, Levi R (1997). "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia" (abstract). J. Pharmacol. Exp. Ther. 283 (2): 494–500. PMID 9353362. http://jpet.aspetjournals.org/cgi/content/abstract/283/2/494.
- ^ Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG (1999). "Cloning and functional expression of the human histamine H3 receptor" (abstract). Mol. Pharmacol. 55 (6): 1101–7. PMID 10347254. http://molpharm.aspetjournals.org/cgi/content/abstract/55/6/1101.
- ^ Levi R, Smith NC (2000). "Histamine H3-receptors: a new frontier in myocardial ischemia" (abstract). J. Pharmacol. Exp. Ther. 292 (3): 825–30. PMID 10688593. http://jpet.aspetjournals.org/cgi/content/abstract/292/3/825.
- ^ 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 (2002). "Behavioral characterization of mice lacking histamine H3 receptors". Mol. Pharmacol. 62 (2): 389–97. doi:10.1124/mol.62.2.389. PMID 12130692.
Further reading
- Hill SJ, Ganellin CR, Timmerman H, et al. (1997). "International Union of Pharmacology. XIII. Classification of histamine receptors". Pharmacol. Rev. 49 (3): 253–78. PMID 9311023.
- Malinowska B, Godlewski G, Schlicker E (1998). "Histamine H3 receptors--general characterization and their function in the cardiovascular system". J. Physiol. Pharmacol. 49 (2): 191–211. PMID 9670104.
- Leurs R, Hoffmann M, Wieland K, Timmerman H (2000). "H3 receptor gene is cloned at last". Trends Pharmacol. Sci. 21 (1): 11–2. doi:10.1016/S0165-6147(99)01411-X. PMID 10637648.
- Leurs R, Bakker RA, Timmerman H, de Esch IJ (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 (2006). "Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders". Mol. Interv. 6 (2): 77–88, 59. doi:10.1124/mi.6.2.5. PMID 16565470.
- Lovenberg TW, Roland BL, Wilson SJ, et al. (1999). "Cloning and functional expression of the human histamine H3 receptor". Mol. Pharmacol. 55 (6): 1101–7. PMID 10347254.
- Nakamura T, Itadani H, Hidaka Y, et al. (2001). "Molecular cloning and characterization of a new human histamine receptor, HH4R". Biochem. Biophys. Res. Commun. 279 (2): 615–20. doi:10.1006/bbrc.2000.4008. PMID 11118334.
- Cogé F, Guénin SP, Audinot V, et al. (2001). "Genomic organization and characterization of splice variants of the human histamine H3 receptor". Biochem. J. 355 (Pt 2): 279–88. doi:10.1042/0264-6021:3550279. PMC 1221737. PMID 11284713. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1221737.
- Silver RB, Poonwasi KS, Seyedi N, et al. (2002). "Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings". Proc. Natl. Acad. Sci. U.S.A. 99 (1): 501–6. doi:10.1073/pnas.012506099. PMC 117589. PMID 11752397. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=117589.
- Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature 414 (6866): 865–71. doi:10.1038/414865a. PMID 11780052.
- Wiedemann P, Bönisch H, Oerters F, Brüss M (2002). "Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations". Journal of neural transmission (Vienna, Austria : 1996) 109 (4): 443–53. doi:10.1007/s007020200036. PMID 11956964.
- Wellendorph P, Goodman MW, Burstein ES, et al. (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.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Lozeva V, Tuomisto L, Tarhanen J, Butterworth RF (2004). "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". J. Hepatol. 39 (4): 522–7. doi:10.1016/S0168-8278(03)00353-2. PMID 12971961.
- Lippert U, Artuc M, Grützkau A, et al. (2004). "Human skin mast cells express H2 and H4, but not H3 receptors". J. Invest. Dermatol. 123 (1): 116–23. doi:10.1111/j.0022-202X.2004.22721.x. PMID 15191551.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
External links
- "Histamine Receptors: H3". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307.
- H3+receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
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Cell surface receptor: G protein-coupled receptors
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Class A:
Rhodopsin like |
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| Class B: Secretin like |
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Orphan
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- GPR (56
- 64
- 97
- 98
- 110
- 111
- 112
- 113
- 114
- 115
- 116
- 123
- 124
- 125
- 126
- 128
- 133
- 143
- 144
- 155
- 157)
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Other
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- Brain-specific angiogenesis inhibitor (1
- 2
- 3)
- Cadherin (1
- 2
- 3)
- Calcitonin
- CALCRL
- CD97
- Corticotropin-releasing hormone (1
- 2)
- EMR (1
- 2
- 3)
- Glucagon (GR
- GIPR
- GLP1R
- GLP2R)
- Growth hormone releasing hormone
- PACAPR1
- GPR
- Latrophilin (1
- 2
- 3
- ELTD1)
- Methuselah-like proteins
- Parathyroid hormone (1
- 2)
- Secretin
- Vasoactive intestinal peptide (1
- 2)
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Class C: Metabotropic
glutamate / pheromone |
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Taste
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- TAS1R (1
- 2
- 3)
- TAS2R (1
- 3
- 4
- 5
- 8
- 9
- 10
- 12
- 13
- 14
- 16
- 19
- 20
- 30
- 31
- 38
- 39
- 40
- 41
- 42
- 43
- 45
- 46
- 50)
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Other
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- Calcium-sensing receptor
- GABA B (1
- 2)
- Glutamate receptor (Metabotropic glutamate (1
- 2
- 3
- 4
- 5
- 6
- 7
- 8))
- GPRC6A
- GPR (156
- 158
- 179)
- RAIG (1
- 2
- 3
- 4)
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Class F:
Frizzled / Smoothened |
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Frizzled
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- Frizzled (1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10)
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Smoothened
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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Histaminergics
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| Receptor |
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H1
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- Agonists: 2-Pyridylethylamine
- Betahistine
- Histamine
- HTMT
- UR-AK49
Antagonists: 1st generation: 4-Methyldiphenhydramine
- Alimemazine
- Antazoline
- Azatadine
- Bamipine
- Benzatropine/Benztropine
- Bepotastine
- Bromazine
- Brompheniramine
- Buclizine
- Captodiame
- Carbinoxamine
- Chlorcyclizine
- Chloropyramine
- Chlorothen
- Chlorphenamine
- Chlorphenoxamine
- Cinnarizine
- Clemastine
- Clobenzepam
- Clocinizine
- Cyclizine
- Cyproheptadine
- Dacemazine
- Deptropine
- Dexbrompheniramine
- Dexchlorpheniramine
- Dimenhydrinate
- Dimetindene
- Diphenhydramine
- Diphenylpyraline
- Doxylamine
- Embramine
- Etodroxizine
- Etybenzatropine/Ethylbenztropine
- Etymemazine
- Flunarizine
- Histapyrrodine
- Homochlorcyclizine
- Hydroxyethylpromethazine
- Hydroxyzine
- Isopromethazine
- Isothipendyl
- Meclozine
- Mepyramine/Pyrilamine
- Mequitazine
- Methafurylene
- Methapyrilene
- Methdilazine
- Moxastine
- Niaprazine
- Orphenadrine
- Oxatomide
- Oxomemazine
- Phenindamine
- Pheniramine
- Phenyltoloxamine
- Pimethixene
- Piperoxan
- Pipoxizine
- Promethazine
- Propiomazine
- Pyrrobutamine
- Talastine
- Thenalidine
- Thenyldiamine
- Thiazinamium
- Thonzylamine
- Tolpropamine
- Tripelennamine
- Triprolidine
- 2nd generation: Acrivastine
- Alinastine
- Astemizole
- Azelastine
- Bamirastine
- Barmastine
- Bepiastine
- Bepotastine
- Bilastine
- Cabastinen
- Carebastine
- Cetirizine
- Clemastine
- Clemizole
- Clobenztropine
- Dorastine
- Ebastine
- Emedastine
- Epinastine
- Flezelastine
- Ketotifen
- Latrepirdine
- Levocabastine
- Linetastine
- Loratadine
- Mapinastine
- Mebhydrolin
- Mizolastine
- Moxastine
- Noberastine
- Octastine
- Olopatadine
- Perastine
- Piclopastine
- Rocastine
- Rupatadine
- Setastine
- Talastine
- Temelastine
- Terfenadine
- Zepastine
- 3rd generation: Desloratadine
- Fexofenadine
- Levocetirizine
- Ungrouped: Belarizine
- Efletirizine
- Elbanizine
- Flotrenizine
- Medrylamine
- Napactadine
- Pibaxizine
- Tagorizine
- Trelnarizine
- Trenizine
- Vapitadine
- Miscellaneous: Tricyclic antidepressants (amitriptyline,
- doxepin,
- trimipramine, etc)
- Tetracyclic antidepressants (mianserin,
- mirtazapine, etc)
- Typical antipsychotics (chlorpromazine,
- thioridazine, etc)
- Atypical antipsychotics (clozapine,
- olanzapine,
- quetiapine, etc)
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H2
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- Agonists: Amthamine
- Betazole
- Dimaprit
- Histamine
- HTMT
- Impromidine
- UR-AK49
Antagonists: Bisfentidine
- Burimamide
- Cimetidine
- Dalcotidine
- Donetidine
- Ebrotidine
- Etintidine
- Famotidine
- Lafutidine
- Lamtidine
- Lavoltidine/Loxtidine
- Lupitidine
- Metiamide
- Mifentidine
- Niperotidine
- Nizatidine
- Osutidine
- Oxmetidine
- Pibutidine
- Quisultazine/Quisultidine
- Ramixotidine
- Ranitidine
- Roxatidine
- Sufotidine
- Tiotidine
- Tuvatidine
- Venritidine
- Xaltidine
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H3
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- Agonists: α-Methylhistamine
- Cipralisant
- Histamine
- Imetit
- Immepip
- Immethridine
- Methimepip
- Proxyfan
Antagonists: A-349,821
- A-423,579
- ABT-239
- Betahistine
- Burimamide
- Ciproxifan
- Clobenpropit
- Conessine
- GSK-189,254
- Impentamine
- Iodophenpropit
- JNJ-5,207,852
- MK-0249
- NNC-38-1,049
- PF-03654746
- Pitolisant
- SCH-79,687
- Thioperamide
- VUF-5,681
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H4
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- Agonists: 4-Methylhistamine
- Histamine
- VUF-8,430
Antagonists: JNJ-7,777,120
- Thioperamide
- VUF-6,002
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| Transporter |
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VMAT
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- Inhibitors: Ibogaine
- Reserpine
- Tetrabenazine
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| Enzyme |
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HDC
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- Inhibitors: Catechin
- Meciadanol
- Naringenin
- Tritoqualine
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DAO
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- Inhibitors: Aminoguanidine
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| Others |
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Endogenous
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- Histamine; Precursors: L-Histidine; Cofactors: Vitamin B6
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