histamine receptor H3
|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 by "feedback inhibition of histamine synthesis and release as well." 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
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.
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)
There are at least six H3 receptor isoforms in the human, and up to 12 discovered so far. In rats there has been six H3 receptor subtypes reported 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.
- 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)
H3 receptors agonists and antagonists
Currently no therapeutic products selective for H3 receptors. Some, though not totally selective, are:
- Addition of methy groups to the α and β side chain of histamine can result in potent H3-receptor agonists.
see antihistamines - H3-receptor antagonists
- ↑ Abbott's H3 histamine receptor antagonist, ABT-239, a candidate treatment of cognitive disorders, ADHD, Alzheimer's and schizophrenia
- ↑ 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)
- ↑ 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.
- ↑ Bakker RA (2004). "Histamine H3-receptor isoforms". Inflammation Research 53 (10): 509-16. PMID 15597144. Fulltext options
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ T.W. Lovenberg et al., Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55 (1999), pp. 1101–1107
- ↑ 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
- ↑ 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
- ↑ Development of trans-2-(1H-Imidazol-4-yl) Cyclopropane Derivatives as New High-Affinity Histamine H3 Receptor Ligands.
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