“Histamine H3 receptor”的意思、由来-开放百科全书

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, histamine and serotonin.

The gene sequence for H₃ receptors expresses only about 22% and 20% homology with both H₁ and H₂ receptors respectively.

There is a lot of interest in the histamine H3 receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive H3R-disorders and especially its location in the central nervous system.^[2]^[3]

Tissue distribution

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.^[3]

The diverse expression of H₃ receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.

Isoforms

There are at least six H₃ receptor isoforms in the human, and more than 20 discovered so far.^[5] In rats there have been six H₃receptor subtypes identified so far. Mice also have three reported isoforms.^[6] 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.

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:

Antagonists

Therapeutic potential

The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R disfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters.^[2]^[10]^[11] Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and (drug)addictions.^[2]^[11]

This receptor has been proposed as a target for treating sleep disorders.^[12] The receptor has also been proposed as a target for treating neuropathic pain.^[13]

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).^[14]^[15]

There is also evidence that the H3-receptor plays an important role in Tourette syndrome.^[16] Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.^[17]^[18]^[19] The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.^[20]

History

See also

References

1. ^{{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 | doi = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/38/5/610 | format = abstract }}
2. ^¹²Rapanelli, 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
3. ^{{cite web | url = http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980 | title = InterPro: IPR003980 Histamine H3 receptor | authorlink = | date = | format = | work = InterPro | publisher = European Bioinformatics Institute | pages = | archiveurl = | archivedate = | quote = | accessdate = }}
4. ^{{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 }}
5. ^{{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 }}
6. ^{{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 }}
7. ^{{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.}}
8. ^{{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 | doi = | url = http://jpet.aspetjournals.org/cgi/content/abstract/289/2/1160 | format = abstract }}
9. ^{{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.}}
10. ^Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” Neuropharmacology 106 (July 2016): 74–84
11. ^¹Sadek, 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
12. ^{{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 }}
13. ^{{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 }}
14. ^{{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 }}
15. ^¹Sadek, 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
16. ^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
17. ^Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” Neuropharmacology 106 (July 2016): 74–84
18. ^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
19. ^Rapanelli, Maximiliano, and Christopher Pittenger. “Histamine and Histamine Receptors in Tourette Syndrome and Other Neuropsychiatric Conditions.” Neuropharmacology 106 (July 2016): 85–90
20. ^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
21. ^{{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 }}
22. ^{{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 }}
23. ^{{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 | doi = | url = http://jpet.aspetjournals.org/cgi/content/abstract/283/2/494 | format = abstract }}
24. ^{{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| url = http://molpharm.aspetjournals.org/cgi/content/abstract/55/6/1101 | format = abstract }}
25. ^{{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 | doi = | url = http://jpet.aspetjournals.org/cgi/content/abstract/292/3/825 | format = abstract }}
26. ^{{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 }}