Histamine H3 receptor explained

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 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 much interest in the histamine H₃ 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.^[2]

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.^[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.

H₃ receptors are thought to play a part in the control of satiety.^[4]

Isoforms

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

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)^[7]
• 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:^[8]

• A-304121 (No tolerance formation, silent antagonist)^[9]
• A-349,821^[10]
• ABT-239
• Betahistine (also weak H₁ agonist)
• Burimamide (also weak H₂ antagonist)
• Ciproxifan
• Clobenpropit (also H₄ antagonist)
• Conessine
• Failproxifan (No tolerance formation)
• Impentamine
• Iodophenpropit
• Irdabisant
• Pitolisant
• Thioperamide (also H₄ antagonist)
• VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)

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.^{[11] [12]} Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions.

This receptor has been proposed as a target for treating sleep disorders.^[13] The receptor has also been proposed as a target for treating neuropathic pain.^[14]

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).^{[15] [16]}

There is also evidence that the H3-receptor plays an important role in Tourette syndrome.^[17] Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.^{[18] [19] [20]} The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.^[21]

History

• 1983 The H₃ receptor is pharmacologically identified.^[22]
• 1988 H₃ receptor found to mediate inhibition of serotonin release in rat brain cortex.^[23]
• 1997 H₃ receptors shown to modulate ischemic norepinephrine release in animals.^[24]
• 1999 H₃ receptor cloned^[25]
• 2000 H₃ receptors called "new frontier in myocardial ischemia"^[26]
• 2002 H₃^(-/-) mice (mice that do not have this receptor)^[27]

See also

• Antihistamine – histamine receptor antagonists
• H₃-receptor antagonist
• Histamine H₁-receptor
• Histamine H₂-receptor
• Histamine H₄-receptor

Further reading

• Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL . International Union of Pharmacology. XIII. Classification of histamine receptors . Pharmacological Reviews . 49 . 3 . 253–78 . Sep 1997 . 9311023 .
• Malinowska B, Godlewski G, Schlicker E . Histamine H3 receptors--general characterization and their function in the cardiovascular system . Journal of Physiology and Pharmacology . 49 . 2 . 191–211 . Jun 1998 . 9670104 .
• Leurs R, Hoffmann M, Wieland K, Timmerman H . H3 receptor gene is cloned at last . Trends in Pharmacological Sciences . 21 . 1 . 11–2 . Jan 2000 . 10637648 . 10.1016/S0165-6147(99)01411-X .
• Leurs R, Bakker RA, Timmerman H, de Esch IJ . The histamine H3 receptor: from gene cloning to H3 receptor drugs . Nature Reviews. Drug Discovery . 4 . 2 . 107–20 . Feb 2005 . 15665857 . 10.1038/nrd1631 . 32781560 . free .
• Esbenshade TA, Fox GB, Cowart MD . Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders . Molecular Interventions . 6 . 2 . 77–88, 59 . Apr 2006 . 16565470 . 10.1124/mi.6.2.5 .
• Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG . Cloning and functional expression of the human histamine H3 receptor . Molecular Pharmacology . 55 . 6 . 1101–7 . Jun 1999 . 10347254 . 10.1124/mol.55.6.1101. 25542667 .
• Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K . Molecular cloning and characterization of a new human histamine receptor, HH4R . Biochemical and Biophysical Research Communications . 279 . 2 . 615–20 . Dec 2000 . 11118334 . 10.1006/bbrc.2000.4008 .
• Cogé F, Guénin SP, Audinot V, Renouard-Try A, Beauverger P, Macia C, Ouvry C, Nagel N, Rique H, Boutin JA, Galizzi JP . Genomic organization and characterization of splice variants of the human histamine H3 receptor . The Biochemical Journal . 355 . Pt 2 . 279–88 . Apr 2001 . 11284713 . 1221737 . 10.1042/0264-6021:3550279 .
• Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R . 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 . Jan 2002 . 11752397 . 117589 . 10.1073/pnas.012506099 . 2002PNAS...99..501S . free .
• Wiedemann P, Bönisch H, Oerters F, Brüss M . Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations . Journal of Neural Transmission . 109 . 4 . 443–53 . Apr 2002 . 11956964 . 10.1007/s007020200036 . 32434148 .
• Wellendorph P, Goodman MW, Burstein ES, Nash NR, Brann MR, Weiner DM . Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor . Neuropharmacology . 42 . 7 . 929–40 . Jun 2002 . 12069903 . 10.1016/S0028-3908(02)00041-2 . 54326678 .
• Lozeva V, Tuomisto L, Tarhanen J, Butterworth RF . 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 . Oct 2003 . 12971961 . 10.1016/S0168-8278(03)00353-2 .
• 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 . Human skin mast cells express H2 and H4, but not H3 receptors . The Journal of Investigative Dermatology . 123 . 1 . 116–23 . Jul 2004 . 15191551 . 10.1111/j.0022-202X.2004.22721.x . free .

External links

• Web site: Histamine Receptors: H₃ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2006-07-20 . 2013-12-25 . https://web.archive.org/web/20131225114708/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2307 . dead .

Notes and References

1. West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA . Identification of two H3-histamine receptor subtypes . Molecular Pharmacology . 38 . 5 . 610–3 . Nov 1990 . 2172771 . abstract .
2. 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
3. Web site: InterPro: IPR003980 Histamine H3 receptor . . European Bioinformatics Institute .
4. Attoub S, Moizo L, Sobhani I, Laigneau JP, Lewin MJ, Bado A . The H3 receptor is involved in cholecystokinin inhibition of food intake in rats . Life Sciences . 69 . 4 . 469–78 . Jun 2001 . 11459437 . 10.1016/S0024-3205(01)01138-9 .
5. Bakker RA . Histamine H3-receptor isoforms . Inflammation Research . 53 . 10 . 509–16 . Oct 2004 . 15597144 . 10.1007/s00011-004-1286-9 . 9630188 .
6. Rouleau A, Héron A, Cochois V, Pillot C, Schwartz JC, Arrang JM . Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms . Journal of Neurochemistry . 90 . 6 . 1331–8 . Sep 2004 . 15341517 . 10.1111/j.1471-4159.2004.02606.x . 29078902 . free .
7. 15821027 . 10.1124/jpet.104.078865 . 314 . 1 . G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations . July 2005 . J. Pharmacol. Exp. Ther. . 271–81 . Krueger KM, Witte DG, Ireland-Denny L et al.. 20470970 .
8. Tedford CE, Phillips JG, Gregory R, Pawlowski GP, Fadnis L, Khan MA, Ali SM, Handley MK, Yates SL . Development of trans-2-[1H-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H3 receptor ligands ]. The Journal of Pharmacology and Experimental Therapeutics . 289 . 2 . 1160–8 . May 1999 . 10215700 . abstract .
9. Pan JB, Yao BB, Miller TR, Kroeger PE, Bennani YL, Komater VA, Esbenshade TA, Hancock AA, Decker MW, Fox GB . Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121 . Life Sciences . 79 . 14 . 1366–1379 . August 2006 . 16730751 . 10.1016/j.lfs.2006.04.002 .
10. 15294456 . 10.1016/j.bcp.2004.05.048 . 68 . 5 . Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist . September 2004 . Biochem. Pharmacol. . 933–45 . Esbenshade TA, Fox GB, Krueger KM et al..
11. Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” Neuropharmacology 106 (July 2016): 74–84
12. 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
13. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P . The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders . Trends in Pharmacological Sciences . 25 . 12 . 618–25 . Dec 2004 . 15530639 . 10.1016/j.tips.2004.10.003 .
14. Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, Roberts JC, Medhurst AD, Chessell IP . Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain . Pain . 138 . 1 . 61–9 . Aug 2008 . 18164820 . 10.1016/j.pain.2007.11.006 . 43724064 .
15. Leurs R, Bakker RA, Timmerman H, de Esch IJ . The histamine H3 receptor: from gene cloning to H3 receptor drugs . Nature Reviews. Drug Discovery . 4 . 2 . 107–20 . Feb 2005 . 15665857 . 10.1038/nrd1631 . 32781560 . free .
16. 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
17. 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
18. Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” Neuropharmacology 106 (July 2016): 74–84
19. 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
20. Rapanelli, Maximiliano, and Christopher Pittenger. “Histamine and Histamine Receptors in Tourette Syndrome and Other Neuropsychiatric Conditions.” Neuropharmacology 106 (July 2016): 85–90
21. 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
22. Arrang JM, Garbarg M, Schwartz JC . Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor . Nature . 302 . 5911 . 832–7 . Apr 1983 . 6188956 . 10.1038/302832a0 . 1983Natur.302..832A . 4302564 .
23. Schlicker E, Betz R, Göthert M . Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex . Naunyn-Schmiedeberg's Archives of Pharmacology . 337 . 5 . 588–90 . May 1988 . 3412497 . 10.1007/BF00182737 . 24168192 .
24. Hatta E, Yasuda K, Levi R . Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia . The Journal of Pharmacology and Experimental Therapeutics . 283 . 2 . 494–500 . Nov 1997 . 9353362 . abstract .
25. Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG . Cloning and functional expression of the human histamine H3 receptor . Molecular Pharmacology . 55 . 6 . 1101–7 . Jun 1999 . 10347254 . 10.1124/mol.55.6.1101. 25542667 .
26. Levi R, Smith NC . Histamine H(3)-receptors: a new frontier in myocardial ischemia . The Journal of Pharmacology and Experimental Therapeutics . 292 . 3 . 825–30 . Mar 2000 . 10688593 . abstract .
27. 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 . Behavioral characterization of mice lacking histamine H(3) receptors . Molecular Pharmacology . 62 . 2 . 389–97 . Aug 2002 . 12130692 . 10.1124/mol.62.2.389 . 25583387 .