histamine H3 receptor

ヒスタミンH3受容体、ヒスタミンH3レセプター

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H3 receptor

WordNet

1. the 8th letter of the Roman alphabet (同)h
2. amine formed from histidine that stimulates gastric secretions and dilates blood vessels; released by the human immune system during allergic reactions
3. a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

1. hydrogenの化学記号
2. 鉛筆の硬度 / 《俗》heroin
3. ヒスタミン(子宮収縮・血圧降下の薬)
4. =sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/11 05:16:48」(JST)

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Histamine receptor H3
Identifiers
Symbols	HRH3 ; GPCR97; HH3R
External IDs	OMIM: 604525 MGI: 2139279 HomoloGene: 5232 IUPHAR: 264 ChEMBL: 264 GeneCards: HRH3 Gene
Gene ontology Molecular function • histamine receptor activity • histamine binding Cellular component • plasma membrane • integral component of plasma membrane Biological process • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • negative regulation of adenylate cyclase activity • neurotransmitter secretion • sensory perception of chemical stimulus • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • negative regulation of glutamate secretion • regulation of norepinephrine secretion • negative regulation of serotonin secretion • cognition Sources: Amigo / QuickGO
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	NP_598610
Location (UCSC)	Chr 20: 62.21 – 62.22 Mb	Chr 2: 180.1 – 180.1 Mb
PubMed search	[1]	[2]

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. 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

• 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 G_i 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.

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.

Isoforms

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

• (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)
• 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

These include:

• A-349,821
• ABT-239
• Betahistine (also weak H₁ agonist)
• Burimamide (also weak H₂ antagonist)
• Ciproxifan
• Clobenpropit (also H₄ antagonist)
• Conessine
• Failproxifan (no tolerance formation, like with Ciproxifan)
• Impentamine
• Iodophenpropit
• Irdabisant
• Pitolisant
• 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. The receptor has also been proposed as a target for treating neuropathic pain.

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).

History

• 1983 The H₃ receptor is pharmacologically identified.
• 1988 H₃ receptor found to mediate inhibition of serotonin release in rat brain cortex.
• 1997 H₃ receptors shown to modulate ischemic norepinephrine release in animals.
• 1999 H₃ receptor cloned
• 2000 H₃ receptors called "new frontier in myocardial ischemia"
• 2002 H₃^(-/-) mice (mice that do not have this receptor)

See also

• Histamine_antagonist#H3-receptor_antagonists

References

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 1221737. 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 117589. 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

• "Histamine Receptors: H₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
• H3 receptors at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. アレルギーのin vitro検査の概要 overview of in vitro allergy tests
• 2. 食物アレルギーに対する今後の診断ツール future diagnostic tools for food allergy
• 3. 食物アレルギーに対する今後の治療法 future therapies for food allergy
• 4. 食物アレルギーの診断的評価 diagnostic evaluation of food allergy
• 5. 免疫学的輸血反応 immunologic blood transfusion reactions

English Journal

• Histamine induces chemotaxis and phagocytosis in murine bone marrow-derived macrophages and RAW 264.7 macrophage-like cells via histamine H4-receptor.

• Czerner CP, Klos A, Seifert R, Neumann D.Author information Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.AbstractOBJECTIVE: Expression and function of histamine H4-receptor, an immunomodulatory receptor involved in inflammatory diseases, on murine macrophages, which are vital for immunity, were investigated.
• Inflammation research : official journal of the European Histamine Research Society ... [et al.].Inflamm Res.2014 Mar;63(3):239-47. doi: 10.1007/s00011-013-0694-0. Epub 2013 Dec 8.
• OBJECTIVE: Expression and function of histamine H4-receptor, an immunomodulatory receptor involved in inflammatory diseases, on murine macrophages, which are vital for immunity, were investigated.MATERIALS AND METHODS: The expression pattern of histamine receptors on bone marrow-derived macrophages
• PMID 24316866

• Models for H3 receptor antagonist activity of sulfonylurea derivatives.

• Khatri N1, Madan AK2.Author information 1Faculty of Pharmaceutical Sciences, Pt. B. D. Sharma University of Health Sciences, Rohtak 124001, India.2Faculty of Pharmaceutical Sciences, Pt. B. D. Sharma University of Health Sciences, Rohtak 124001, India. Electronic address: madan_ak@yahoo.com.AbstractThe histamine H3 receptor has been perceived as an auspicious target for the treatment of various central and peripheral nervous system diseases. In present study, a wide variety of 60 2D and 3D molecular descriptors (MDs) were successfully utilized for the development of models for the prediction of antagonist activity of sulfonylurea derivatives for histamine H3 receptors. Models were developed through decision tree (DT), random forest (RF) and moving average analysis (MAA). Dragon software version 6.0.28 was employed for calculation of values of diverse MDs of each analogue involved in the data set. The DT classified and correctly predicted the input data with an impressive non-error rate of 94% in the training set and 82.5% during cross validation. RF correctly classified the analogues into active and inactive with a non-error rate of 79.3%. The MAA based models predicted the antagonist histamine H3 receptor activity with non-error rate up to 90%. Active ranges of the proposed MAA based models not only exhibited high potency but also showed improved safety as indicated by relatively high values of selectivity index. The statistical significance of the models was assessed through sensitivity, specificity, non-error rate, Matthew's correlation coefficient and intercorrelation analysis. Proposed models offer vast potential for providing lead structures for development of potent but safe H3 receptor antagonist sulfonylurea derivatives.
• Journal of molecular graphics & modelling.J Mol Graph Model.2014 Mar;48:87-95. doi: 10.1016/j.jmgm.2013.12.005. Epub 2013 Dec 25.
• The histamine H3 receptor has been perceived as an auspicious target for the treatment of various central and peripheral nervous system diseases. In present study, a wide variety of 60 2D and 3D molecular descriptors (MDs) were successfully utilized for the development of models for the prediction o
• PMID 24434018

• Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition.

• Brown DG, Bernstein PR, Griffin A, Wesolowski S, Labrecque D, Tremblay MC, Sylvester M, Mauger R, Edwards PD, Throner SR, Folmer JJ, Cacciola J, Scott C, Lazor LA, Pourashraf M, Santhakumar V, Potts WM, Sydserff S, Giguère P, Lévesque C, Dasser M, Groblewski T.Author information AstraZeneca CNS Discovery Research , 1800 Concord Pike, Wilmington, Delaware 19850, United States.AbstractA new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
• Journal of medicinal chemistry.J Med Chem.2014 Feb 13;57(3):733-58. doi: 10.1021/jm4014828. Epub 2014 Jan 27.
• A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demons
• PMID 24410637

Japanese Journal

• Involvement of histaminergic system in the anxiolytic-like activities of Morus alba L. leaves in mice

• Lee Seungheon,Kim Dong Hyun,Lee Ji Hye,Ko Eun Seong,Oh Won Bo,Seo Yong Taek,Jang Young Pyo,Ryu Jong Hoon,Jung Ji Wook
• Biological and Pharmaceutical Bulletin, 2013
• … In addition, the anxiolytic-like effects of EMA were abolished by thioperamide (10 mg/kg, i.p), which is a histamine H3 receptor antagonist. …
• NAID 130003361548

• 肥満細胞株RBL-2H3のアレルギー関連遺伝子発現に及ぼす栄養因子の影響

• 松村 愛子,岡野 真知子,妻木 陽子,坂井 堅太郎,MATSUMURA Aiko,OKANO Ｍachiko,TSUMAKI Yoko,SAKAI Kentaro,マツムラ アイコ,オカノ マチコ,ツマキ ヨウコ,サカイ ケンタロウ
• 広島女学院大学生活科学部紀要 (19), 61-71, 2012-03-09
• … Mast cells are central effector that cause immediate hypersensitive responses to onset of allergy syndromes through the IgE mediated release of a variety of chemical materials.Histamine is synthesized in mast cells and basophils by the action of histidine decarboxylase (HDC) on L-histidine, the major chemical mediator that implicated in mechanism of allergic reactions, such as vasodilation, branchial smooth muscle contraction and mucus secretion. …
• NAID 120005344837

• Roles of Histamine in Exercise-Induced Fatigue: Favouring Endurance and Protecting against Exhaustion

• Niijima-Yaoita Fukie,Tsuchiya Masahiro,Ohtsu Hiroshi [他],Yanai Kazuhiko,Sugawara Shunji,Endo Yasuo,Tadano Takeshi
• Biological and Pharmaceutical Bulletin 35(1), 91-97, 2012
• … Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. … Histamine is released from either mast cells or non-mast cells. … In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. …
• NAID 130001872348

Related Links

• KAKEN - ヒスタミンH3受容体をターゲットとした創薬;喘息,痴呆 ...

ヒスタミンH3受容体は、中枢ヒスタミン神経系のシナプス前部に存在するオートレセプターで、ヒスタミンの遊離、合成を調節している。最近、末梢にも、また、他の神経系にも存在するといわれている。本研究では、ヒスタミンと関連する ...

• DrugBank: Histamine H3 receptor

General Function Involved in rhodopsin-like receptor activity Specific Function The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of ...

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「H3 receptor」

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H3受容体、H3レセプター

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histamine H3 receptor

「H3 receptor」

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H3受容体、H3レセプター

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histamine H3 receptor

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