Histamine H3 receptor

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 control histamine turnover by feedback inhibition of histamine synthesis and release.^[5] 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.

HRH3
Identifiers
Aliases	HRH3, GPCR97, HH3R, histamine receptor H3
External IDs	OMIM: 604525; MGI: 2139279; HomoloGene: 5232; GeneCards: HRH3; OMA:HRH3 - orthologs
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20q13.33 Start 62,214,960 bp[1] End 62,220,278 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 H4|2 102.62 cM Start 179,741,258 bp[2] End 179,746,281 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen nucleus accumbens right hemisphere of cerebellum caudate nucleus anterior cingulate cortex testicle right frontal lobe Hypothalamus Brodmann area 9 prefrontal cortex Top expressed in superior frontal gyrus primary visual cortex dentate gyrus of hippocampal formation granule cell lumbar subsegment of spinal cord medial dorsal nucleus nucleus of stria terminalis subiculum nucleus accumbens prefrontal cortex olfactory tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity histamine receptor activity G protein-coupled serotonin receptor activity G protein-coupled acetylcholine receptor activity neurotransmitter receptor activity Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane presynapse dendrite Biological process regulation of norepinephrine secretion regulation of neurotransmitter levels negative regulation of glutamate secretion cognition G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger negative regulation of serotonin secretion neurotransmitter secretion signal transduction negative regulation of adenylate cyclase activity G protein-coupled receptor signaling pathway adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway chemical synaptic transmission G protein-coupled serotonin receptor signaling pathway Sources:Amigo / QuickGO
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: 179.74 – 179.75 Mb PubMed search [3] [4]
Wikidata
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The gene sequence for H₃ receptors expresses only about 22% and 20% homology with both H₁ and H₂ receptors respectively.

There is much interest in the histamine H₃ receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive disorders and especially its location in the central nervous system.^[6][7]

Tissue distribution

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

Function

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. H₃ receptors function as presynaptic autoreceptors on histamine-containing neurons.^[8]

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.^[9]

Isoforms

There are at least six H₃ receptor isoforms in the human, and more than 20 discovered so far.^[10] In rats six H₃receptor subtypes have been identified so far. Mice also have three reported isoforms.^[11] 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.^{[medical citation needed]}

Pharmacology

Histamine

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:

• (R)-α-methylhistamine
• Cipralisant (initially assessed as H₃ antagonist, later found to be an agonist, shows functional selectivity, activating some G-protein coupled pathways but not others)^[12]
• Imbutamine (also H4 agonist)
• Immepip
• Imetit
• Immethridine
• Methimepip
• Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release)

Antagonists

Main article: H3 receptor antagonist

H₃ receptor antagonists include:^[13]

• A-304121 (No tolerance formation, silent antagonist)^[14]
• A-349,821^[15]
• ABT-239
• Betahistine (also weak H₁ agonist)
• Burimamide (also weak H₂ antagonist)
• Ciproxifan
• Clobenpropit (also H₄ antagonist)
• Conessine
• Failproxifan^{[citation needed]} (No tolerance formation)^{[citation needed]}
• Impentamine
• Iodophenpropit
• Irdabisant
• Pitolisant
• Thioperamide (also H₄ antagonist)
• VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)

Therapeutic potential

The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R dysfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters.^[6][16][17] Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions.^[6][17]

This receptor has been proposed as a target for treating sleep disorders.^[18] The receptor has also been proposed as a target for treating neuropathic pain.^[19]

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).^[20][7]

There is also evidence that the H3-receptor plays an important role in Tourette syndrome.^[21] Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.^[22][23][24] The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.^[25]

History

• 1983: The H₃ receptor is pharmacologically identified.^[26]
• 1988: H₃ receptor found to mediate inhibition of serotonin release in rat brain cortex.^[27]
• 1997: H₃ receptors shown to modulate ischemic norepinephrine release in animals.^[28]
• 1999: H₃ receptor cloned^[29]
• 2000: H₃ receptors called "new frontier in myocardial ischemia"^[30]
• 2002: H₃^(-/-) mice (mice that do not have this receptor)^[31]

See also

• Antihistamine – histamine receptor antagonists
• H₃-receptor antagonist
• Histamine H₁-receptor
• Histamine H₂-receptor
• Histamine H₄-receptor