Histamine H3 receptor

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Histamine receptor H3
Identifiers
Symbols HRH3 ; GPCR97; HH3R
External IDs OMIM604525 MGI2139279 HomoloGene5232 IUPHAR: 264 ChEMBL: 264 GeneCards: HRH3 Gene
RNA expression pattern
PBB GE HRH3 220447 at tn.png
PBB GE HRH3 221663 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 11255 99296
Ensembl ENSG00000101180 ENSMUSG00000039059
UniProt Q9Y5N1 P58406
RefSeq (mRNA) NM_007232 NM_133849
RefSeq (protein) NP_009163 NP_598610
Location (UCSC) Chr 20:
62.21 – 62.22 Mb
Chr 2:
180.1 – 180.1 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, 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

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 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.

Pharmacology

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

  • 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

References

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  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
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  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
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Further reading

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External links