Histamine H3 receptor

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Histamine receptor H3
Identifiers
SymbolsHRH3; GPCR97; HH3R
External IDsOMIM: 604525 MGI: 2139279 HomoloGene: 5232 IUPHAR: H3 GeneCards: HRH3 Gene
RNA expression pattern
250px
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez1125599296
EnsemblENSG00000101180ENSMUSG00000039059
UniProtQ9Y5N1Q3U1A2
RefSeq (mRNA)NM_007232NM_133849
RefSeq (protein)NP_009163NP_598610
Location (UCSC)Chr 20:
60.22 - 60.23 Mb		Chr 2:
180.03 - 180.03 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.[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, and serotonin.

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

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.[2]

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.[3]

Isoforms

There are at least six H3 receptor isoforms in the human, and up to 12 discovered so far.[4] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.[5] 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

File:Histamine.png
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:

Antagonists

These include:[7]

Therapeutic potential

This receptor has been proposed as a target for treating sleep disorders.[9] The receptor has also been proposed as a target for treating neuropathic pain. [10]

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).[11]

History

See also

References

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Further reading

External links

Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened
de:Histamin-H3-Rezeptor pt:Receptor de histamina H3
  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. 
  2. ↑ "InterPro: IPR003980 Histamine H3 receptor". InterPro. European Bioinformatics Institute. 
  3. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  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. 
  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. 
  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 Sep 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. 
  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. 
  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. 
  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. 
  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. 
  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. 
  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. 
  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. 
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