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Template:PBB 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

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
• Impentamine
• Iodophenpropit
• Irdabisant
• Pitolisant
• Thioperamide (also H₄ antagonist)
• VUF-5681 (4-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

1. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
2. "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
3. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. Bakker RA (2004). "Histamine H₃-receptor isoforms". Inflamm. Res. 53 (10): 509–16. doi:10.1007/s00011-004-1286-9. PMID 15597144.
5. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. 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
7. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. 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
9. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
11. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
16. 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.
17. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

Template:PBB Further reading

External links

• "Histamine Receptors: H₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
• H3+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Template:PBB Controls

• G protein coupled receptors