Biology:Histamine H3 receptor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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][3]

Tissue distribution

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.[4]

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.[5]

Isoforms

There are at least six H3 receptor isoforms in the human, and more than 20 discovered so far.[6] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.[7] 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)[8]
  • 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:[9]

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.[2][12][13] Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions.[2][13]

This receptor has been proposed as a target for treating sleep disorders.[14] The receptor has also been proposed as a target for treating neuropathic pain.[15]

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).[16][3]

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

References

  1. ↑ "Identification of two H3-histamine receptor subtypes" (abstract). Molecular Pharmacology 38 (5): 610–3. Nov 1990. PMID 2172771. http://molpharm.aspetjournals.org/cgi/content/abstract/38/5/610. 
  2. ↑ 2.0 2.1 2.2 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. ↑ 3.0 3.1 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
  4. ↑ "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute. http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003980. 
  5. ↑ "The H3 receptor is involved in cholecystokinin inhibition of food intake in rats". Life Sciences 69 (4): 469–78. Jun 2001. doi:10.1016/S0024-3205(01)01138-9. PMID 11459437. 
  6. ↑ "Histamine H3-receptor isoforms". Inflammation Research 53 (10): 509–16. Oct 2004. doi:10.1007/s00011-004-1286-9. PMID 15597144. 
  7. ↑ "Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms". Journal of Neurochemistry 90 (6): 1331–8. Sep 2004. doi:10.1111/j.1471-4159.2004.02606.x. PMID 15341517. 
  8. ↑ "G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations". J. Pharmacol. Exp. Ther. 314 (1): 271–81. July 2005. doi:10.1124/jpet.104.078865. PMID 15821027. 
  9. ↑ "Development of trans-2-[1H-imidazol-4-yl cyclopropane derivatives as new high-affinity histamine H3 receptor ligands"] (abstract). The Journal of Pharmacology and Experimental Therapeutics 289 (2): 1160–8. May 1999. PMID 10215700. http://jpet.aspetjournals.org/cgi/content/abstract/289/2/1160. 
  10. ↑ Pan, Jia Bao; Yao, Betty B.; Miller, Thomas R.; Kroeger, Paul E.; Bennani, Youssef L.; Komater, Victoria A.; Esbenshade, Timothy A.; Hancock, Arthur A. et al. (2006-08-29). "Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121". Life Sciences 79 (14): 1366–1379. doi:10.1016/j.lfs.2006.04.002. ISSN 0024-3205. PMID 16730751. https://pubmed.ncbi.nlm.nih.gov/16730751/. 
  11. ↑ "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist". Biochem. Pharmacol. 68 (5): 933–45. September 2004. doi:10.1016/j.bcp.2004.05.048. PMID 15294456. 
  12. ↑ Bolam, J. Paul, and Tommas J. Ellender. “Histamine and the Striatum.” Neuropharmacology 106 (July 2016): 74–84
  13. ↑ 13.0 13.1 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
  14. ↑ "The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders". Trends in Pharmacological Sciences 25 (12): 618–25. Dec 2004. doi:10.1016/j.tips.2004.10.003. PMID 15530639. 
  15. ↑ "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. doi:10.1016/j.pain.2007.11.006. PMID 18164820. 
  16. ↑ "The histamine H3 receptor: from gene cloning to H3 receptor drugs". Nature Reviews. Drug Discovery 4 (2): 107–20. Feb 2005. doi:10.1038/nrd1631. PMID 15665857. 
  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. ↑ "Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor". Nature 302 (5911): 832–7. Apr 1983. doi:10.1038/302832a0. PMID 6188956. Bibcode: 1983Natur.302..832A. 
  23. ↑ "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. doi:10.1007/BF00182737. PMID 3412497. 
  24. ↑ "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia" (abstract). The Journal of Pharmacology and Experimental Therapeutics 283 (2): 494–500. Nov 1997. PMID 9353362. http://jpet.aspetjournals.org/cgi/content/abstract/283/2/494. 
  25. ↑ "Cloning and functional expression of the human histamine H3 receptor". Molecular Pharmacology 55 (6): 1101–7. Jun 1999. doi:10.1124/mol.55.6.1101. PMID 10347254. 
  26. ↑ "Histamine H(3)-receptors: a new frontier in myocardial ischemia" (abstract). The Journal of Pharmacology and Experimental Therapeutics 292 (3): 825–30. Mar 2000. PMID 10688593. http://jpet.aspetjournals.org/cgi/content/abstract/292/3/825. 
  27. ↑ "Behavioral characterization of mice lacking histamine H(3) receptors". Molecular Pharmacology 62 (2): 389–97. Aug 2002. doi:10.1124/mol.62.2.389. PMID 12130692. 

Further reading

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