H₃ receptor

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histamine receptor H3
Identifiers
Symbol	HRH3
HUGO	5184
Entrez	11255
OMIM	604525
RefSeq	NM_007232
UniProt	Q9Y5N1
Other data
Locus	Chr. 20 pter-p12.1

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^[1] by "feedback inhibition of histamine synthesis and release as well."^[2] The H₃also 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.

Contents 1 Locations of H3 receptors 2 Pharmacology 3 Isoforms 4 History 5 H3 receptors agonists and antagonists 5.1 H3-receptor Agonists 5.2 H3-receptor Antagonists 6 References 7 Further reading 8 External links

[edit] Locations of H₃ receptors

• Central nervous system
• Peripheral nerves
• Heart
• Lungs
• Gastrointestinal tract
• Endothelial cells

[edit] Pharmacology

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.

The gene sequence for H₃ receptors expresses only about 30% homology with both H₁ and H₂ receptors. The diverse expression of H₃ receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters. Because of this, 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 even underway as to whether H₃ receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine)

[edit] Isoforms

There are at least six H₃ receptor isoforms in the human, and up to 12 discovered so far.^[3] In rats there has been six H₃ receptor subtypes reported so far. Mice also have three reported isoforms.^[4] 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.

[edit] History

• 1983 The H₃ receptor is pharmacologically identified.^[5]
• 1988 H₃ receptor found to mediate inhibition of serotonin release in rat brain cortex.^[6]
• 1997 H₃ receptors shown to modulate ischemic norepinephrine release in animals.^[7]
• 1999 H₃ receptor cloned ^[8]
• 2000 H₃ receptors called "new frontier in myocardial ischemia"^[9]
• 2002 H₃^(-/-) mice (mice that do not have this receptor)^[10]

[edit] H₃ receptors agonists and antagonists

[edit] H₃-receptor Agonists

Currently no therapeutic products selective for H₃ receptors. Some, though not totally selective, are:

• R-α-methylhistamine
• Immepip
  • Addition of methy groups to the α and β side chain of histamine can result in potent H₃-receptor agonists.

[edit] H₃-receptor Antagonists

These include:^[11]

• ABT-239
• GT-2331
• Thioperamide
• Clobenpropit

see antihistamines - H₃-receptor antagonists

[edit] References

1. ^ Abbott's H₃ histamine receptor antagonist, ABT-239, a candidate treatment of cognitive disorders, ADHD, Alzheimer's and schizophrenia
2. ^ RE West, A Zweig, NY Shih, MI Siegel, RW Egan and MA Clark (1990). "Identification of two H3-histamine receptor subtypes". Molecular Pharmacology 38 (5): 610-613. PMID 2172771.  Reprint (PDF, subscription required)
3. ^ Bakker RA (2004). "Histamine H3-receptor isoforms". Inflammation Research 53 (10): 509-16. PMID 15597144.  Fulltext options
4. ^ Rouleau A, Heron A, Cochois V, Pillot C, Schwartz JC, Arrang JM. Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms. J Neurochem. 2004 Sep;90(6):1331-8.
5. ^ Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983 Apr 28;302(5911):832-7.
6. ^ Schlicker E, Betz R, Gothert M. Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1988 May;337(5):588-90.
7. ^ Eiichiro Hatta, Keishu Yasuda and Roberto Levi. Activation of Histamine H3 Receptors Inhibits Carrier-Mediated Norepinephrine Release in a Human Model of Protracted Myocardial Ischemia Pharmacology and Experimental Therapeutics Vol. 283, Issue 2, 494-500, 1997
8. ^ T.W. Lovenberg et al., Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55 (1999), pp. 1101–1107
9. ^ Roberto Levi and Neil C. E. Smith (2000). "Histamine H₃-Receptors: A New Frontier in Myocardial Ischemia". Journal of Pharmacology and Experimental Therapeutics 292 (3): 825-830. PMID 10688593.  Fulltext options
10. ^ Toyota H, Dugovic C, Koehl M, Laposky A, Weber C, Ngo K, Wu Y, Lee D, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier A, Turek F, Fung-Leung W, Lovenberg T (2002). "Behavioral characterization of mice lacking histamine H(3) receptors". Mol Pharmacol 62 (2): 389-97. PMID 12130692.  link
11. ^ Development of trans-2-(1H-Imidazol-4-yl) Cyclopropane Derivatives as New High-Affinity Histamine H3 Receptor Ligands.

[edit] Further reading

• 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 Pharmacol Sci. 2004 Dec;25(12):618-25.
• Morgan SL, Baggott JE Jean-Charles Schwartz, Jean-Michel Arrang and Monique Garbarg (2000). "Histamine". In Bloom FE, Kupfer DJ, Psychopharmacology - The Fourth Generation of Progress, 405-433. New York, NY, Raven Press. ISBN 078170166X.

[edit] External links

• IUPHAR GPCR Database - H₃ Histamine Receptor