Histamine H3 receptor

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.

Locations of H₃ receptors

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

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)

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.

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)

H₃ receptors agonists and antagonists

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.

H₃-receptor Antagonists

see antihistamines - H₃-receptor antagonists

References

• Behavioral Characterization of Mice Lacking Histamine H₃ Receptors
• 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.

End Notes

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.{{cite journal}}: CS1 maint: multiple names: authors list (link) Reprint (PDF, subscription required)
3. ^ 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.
4. ^ 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.
5. ^ 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
6. ^ T.W. Lovenberg et al., Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55 (1999), pp. 1101–1107
7. ^ Bakker RA (2004). "Histamine H3-receptor isoforms". Inflammation Research. 53 (10): 509–16. PMID 15597144. Fulltext options
8. ^ 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.
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

Further reading

• Morgan SL, Baggott JE Jean-Charles Schwartz, Jean-Michel Arrang and Monique Garbarg Template:Section:Chapter reference after author

External links

• IUPHAR Receptor Database - H₃ Histamine Receptor
• human histamine receptor H3 on Entrez Gene