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 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.

It has been proposed as a target for treating sleep disorders.

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 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)

Isoforms
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.

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 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-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
These include: see antihistamines - H3-receptor antagonists
 * ABT-239
 * GT-2331
 * Thioperamide
 * Clobenpropit