Histamine H3 receptor

Histamine H3 receptor

Histamine receptor H3
Symbols  ; GPCR97; HH3R
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.


  • Tissue distribution 1
  • Function 2
  • Isoforms 3
  • Pharmacology 4
    • Agonists 4.1
    • Antagonists 4.2
  • Therapeutic potential 5
  • History 6
  • See also 7
  • References 8
  • Further reading 9
  • External links 10

Tissue distribution


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]


There are at least six H3 receptor isoforms in the human, and more than 20 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.



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:


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]


  • 1983 The H3 receptor is pharmacologically identified.[12]
  • 1988 H3 receptor found to mediate inhibition of serotonin release in rat brain cortex.[13]
  • 1997 H3 receptors shown to modulate ischemic norepinephrine release in animals.[14]
  • 1999 H3 receptor cloned[15]
  • 2000 H3 receptors called "new frontier in myocardial ischemia"[16]
  • 2002 H3(-/-) mice (mice that do not have this receptor)[17]

See also


  1. ^ West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA (1990). -histamine receptor subtypes"3"Identification of two H (abstract). Mol. Pharmacol. 38 (5): 610–3.  
  2. ^ "InterPro: IPR003980 Histamine H3 receptor".  
  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.  
  4. ^ Bakker RA (2004). "Histamine H3-receptor isoforms". Inflamm. Res. 53 (10): 509–16.  
  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.  
  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). receptor ligands"3"Development of trans-2-(1H-imidazol-4-yl) cyclopropane derivatives as new high-affinity histamine H (abstract). J. Pharmacol. Exp. Ther. 289 (2): 1160–8.  
  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.  
  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.  
  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.  
  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.  
  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.  
  14. ^ Hatta E, Yasuda K, Levi R (1997). receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia"3"Activation of histamine H (abstract). J. Pharmacol. Exp. Ther. 283 (2): 494–500.  
  15. ^ Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG (1999). receptor"3"Cloning and functional expression of the human histamine H (abstract). Mol. Pharmacol. 55 (6): 1101–7.  
  16. ^ Levi R, Smith NC (2000). -receptors: a new frontier in myocardial ischemia"3"Histamine H (abstract). J. Pharmacol. Exp. Ther. 292 (3): 825–30.  
  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.  

Further reading

  • Hill SJ, Ganellin CR, Timmerman H, et al. (1997). "International Union of Pharmacology. XIII. Classification of histamine receptors". Pharmacol. Rev. 49 (3): 253–78.  
  • Malinowska B, Godlewski G, Schlicker E (1998). "Histamine H3 receptors--general characterization and their function in the cardiovascular system". J. Physiol. Pharmacol. 49 (2): 191–211.  
  • Leurs R, Hoffmann M, Wieland K, Timmerman H (2000). "H3 receptor gene is cloned at last". Trends Pharmacol. Sci. 21 (1): 11–2.  
  • 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.  
  • Esbenshade TA, Fox GB, Cowart MD (2006). "Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders". Mol. Interv. 6 (2): 77–88, 59.  
  • Lovenberg TW, Roland BL, Wilson SJ, et al. (1999). "Cloning and functional expression of the human histamine H3 receptor". Mol. Pharmacol. 55 (6): 1101–7.  
  • Nakamura T, Itadani H, Hidaka Y, et al. (2001). "Molecular cloning and characterization of a new human histamine receptor, HH4R". Biochem. Biophys. Res. Commun. 279 (2): 615–20.  
  • Cogé F, Guénin SP, Audinot V, et al. (2001). "Genomic organization and characterization of splice variants of the human histamine H3 receptor". Biochem. J. 355 (Pt 2): 279–88.  
  • Silver RB, Poonwasi KS, Seyedi N, et al. (2002). "Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings". Proc. Natl. Acad. Sci. U.S.A. 99 (1): 501–6.  
  • Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature 414 (6866): 865–71.  
  • Wiedemann P, Bönisch H, Oerters F, Brüss M (2002). "Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations". Journal of neural transmission (Vienna, Austria : 1996) 109 (4): 443–53.  
  • Wellendorph P, Goodman MW, Burstein ES, et al. (2002). "Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor". Neuropharmacology 42 (7): 929–40.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • Lozeva V, Tuomisto L, Tarhanen J, Butterworth RF (2004). "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". J. Hepatol. 39 (4): 522–7.  
  • Lippert U, Artuc M, Grützkau A, et al. (2004). "Human skin mast cells express H2 and H4, but not H3 receptors". J. Invest. Dermatol. 123 (1): 116–23.  
  • Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7.  

External links

  • "3"Histamine Receptors: H. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
  • H3 receptors at the US National Library of Medicine Medical Subject Headings (MeSH)