Histamine H3 receptor

Histamine H3 receptors are expressed in the is_associated_with::central nervous system and to a lesser extent the is_associated_with::peripheral nervous system, where they act as is_associated_with::autoreceptors in presynaptic is_associated_with::histaminergic is_associated_with::neurons, and also control is_associated_with::histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other is_associated_with::neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to is_associated_with::dopamine, GABA, is_associated_with::acetylcholine, is_associated_with::noradrenaline, is_associated_with::histamine and is_associated_with::serotonin.

The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.

Tissue distribution

 * is_associated_with::Central nervous system
 * is_associated_with::Peripheral nervous system
 * is_associated_with::Heart
 * is_associated_with::Lungs
 * is_associated_with::Gastrointestinal tract
 * is_associated_with::Endothelial cells

Function
Like all histamine receptors the H3 receptor is a is_associated_with::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 is_associated_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 is_associated_with::autoreceptors on histamine-containing neurons.

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.

Isoforms
There are at least six H3 receptor is_associated_with::isoforms in the human, and more than 20 discovered so far. In rats there have been six H3receptor subtypes identified 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.

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
 * is_associated_with::Cipralisant (initially assessed as H3 antagonist, later found to be an agonist, shows is_associated_with::functional selectivity, activating some G-protein coupled pathways but not others)
 * is_associated_with::Imbutamine (also H4 agonist)
 * is_associated_with::Immepip
 * is_associated_with::Imetit
 * is_associated_with::Immethridine
 * is_associated_with::Methimepip
 * is_associated_with::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
These include:
 * is_associated_with::A-349,821
 * is_associated_with::ABT-239
 * is_associated_with::Betahistine (also weak H1 agonist)
 * is_associated_with::Burimamide (also weak H2 antagonist)
 * is_associated_with::Ciproxifan
 * is_associated_with::Conessine
 * is_associated_with::Clobenpropit (also H4 antagonist)
 * is_associated_with::Impentamine
 * is_associated_with::Iodophenpropit
 * is_associated_with::Thioperamide (also H4 antagonist)
 * is_associated_with::VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)

Therapeutic potential
This receptor has been proposed as a target for treating is_associated_with::sleep disorders. The receptor has also been proposed as a target for treating neuropathic is_associated_with::pain.

Because of its ability to modulate other neurotransmitters, H3 receptor is_associated_with::ligands are being investigated for the treatment of numerous neurological conditions, including is_associated_with::obesity (because of the histamine/is_associated_with::orexinergic system interaction), is_associated_with::movement disorders (because of H3 receptor-modulation of dopamine and GABA in the is_associated_with::basal ganglia), is_associated_with::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, is_associated_with::glutamate and histamine).

History

 * 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 is_associated_with::norepinephrine release in animals.
 * 1999 H3 receptor cloned
 * 2000 H3 receptors called "new frontier in is_associated_with::myocardial ischemia"
 * 2002 H3(-/-) mice (mice that do not have this receptor)