H3 receptor
Encyclopedia
Histamine H3 receptors are expressed in the central nervous system
and to a lesser extent the peripheral nervous system
, where they act as autoreceptor
s in presynaptic histaminergic
neuron
s, and also control 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 neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine
, GABA
, acetylcholine
, noradrenaline, and serotonin
.
The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.
, 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.
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.
s. The receptor has also been proposed as a target for treating neuropathic pain
.
Because of its ability to modulate other neurotransmitters, H3 receptor ligand
s are being investigated for the treatment of numerous neurological conditions, including obesity
(because of the histamine/orexin
ergic system interaction), movement disorder
s (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).
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and to a lesser extent the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
, where they act as autoreceptor
Autoreceptor
An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.Canonically, a presynaptic...
s in presynaptic histaminergic
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, and also control histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
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 neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, noradrenaline, and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
.
The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.
Tissue distribution
- Central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
- Peripheral nervous systemPeripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
- HeartHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
- LungLungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s - Gastrointestinal tractGastrointestinal tractThe human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
- Endothelial cells
Function
Like all histamine receptors the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi G-proteinG protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
, so it leads to inhibition of the formation of cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
. 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.
The diverse expression of H3 receptors throughout the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
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 isoforms in the human, and up to 12 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-methylhistamineAlpha-methylhistamineα-Methylhistamine is a histamine agonist selective for the receptor subtype H3. It causes lowering of blood pressure and a decrease of heart rate in animal models....
- CipralisantCipralisantCipralisant is an extremely potent Histamine H3 receptor ligand originally developed by Gliatech...
(initially assessed as H3 antagonist, later found to be an agonist, shows functional selectivityFunctional SelectivityFunctional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
, activating some G-protein coupled pathways but not others) - ImmepipImmepipImmepip is a histamine agonist....
- ImetitImetitImetit is a Histamine H3 receptor agonist....
- ImmethridineImmethridineImmethridine is a histamine agonist selective for the H3 subtype....
- MethimepipMethimepipMethimepip is a histamine agonist which is highly selective for the H3 subtype. It is the N-methyl derivative of immepip....
- ProxyfanProxyfanProxyfan is a histamine H3 receptor ligand which is a "protean agonist", producing different effects ranging from full agonist, to antagonist, to inverse agonist in different tissues, depending on the level of constitutive activity of the histamine H3 receptor. This gives it a complex activity...
(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:- A-349,821A-349,821A-349,821 is a potent and selective histamine H3 receptor antagonist . It has nootropic effects in animal studies, although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research....
- ABT-239ABT-239ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia. ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan,...
- BetahistineBetahistineBetahistine hydrochloride is an antivertigo drug. It was first registered in Europe in 1970 for the treatment of Ménière's disease...
- BurimamideBurimamideBurimamide is an antagonist at the H2 and H3 histamine receptors. It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher. It is a thiourea derivative....
(also weak H2 antagonist) - CiproxifanCiproxifanCiproxifan is an extremely potent histamine H3 inverse agonist/antagonist.The histamine H3 receptor is an inhibitory autoreceptor located on histaminergic nerve terminals, and is believed to be involved in modulating the release of histamine in the brain...
- ConessineConessineConessine is a steroid alkaloid found in a number of plant species from the Apocynaceae family, including Holarrhena floribunda, Holarrhena antidysenterica and Funtumia elastica, several of which are used in traditional herbal medicine as a treatment for amoebic dysentery. It acts as a histamine...
- ClobenpropitClobenpropitClobenpropit is a histamine H3 receptor antagonist. It has neuroprotective effects via stimulation of GABA release in the brain....
(also H4 antagonist) - ImpentamineImpentamineImpentamine is a histamine antagonist selective for the H3 subtype....
- IodophenpropitIodophenpropitIodophenpropit is a histamine antagonist which binds selectively to the H3 subtype. Its 125I radiolabelled form is used for mapping the distribution of H3 receptors in the body....
- ThioperamideThioperamideThioperamide is a potent and selective histamine H3 antagonist that is capable of crossing the blood-brain barrier....
(also H4 antagonist) - VUF-5681VUF-5681VUF-5681 is a potent and selective histamine antagonist which binds selectively to the H3 subtype. However while VUF-5681 blocks the activity of more potent H3 agonists, recent studies suggest that it may have some weak partial agonist activity when administered by itself....
(4-[3-(1H-Imidazol-4-yl)propyl]piperidine)
Therapeutic potential
This receptor has been proposed as a target for treating sleep disorderSleep disorder
A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning...
s. The receptor has also been proposed as a target for treating neuropathic pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
.
Because of its ability to modulate other neurotransmitters, H3 receptor ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s are being investigated for the treatment of numerous neurological conditions, including obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
(because of the histamine/orexin
Orexin
Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains....
ergic system interaction), movement disorder
Movement disorder
Movement disorders include:* Akathisia * Akinesia * Associated Movements * Athetosis...
s (because of H3 receptor-modulation of dopamine and GABA in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
), schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
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).
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 ischemicIschemiaIn medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
release in animals. - 1999 H3 receptor cloned
- 2000 H3 receptors called "new frontier in myocardial ischemiaMyocardial ischemiaMyocardial ischemia is an imbalance between myocardial oxygen supply and demand. Left untreated, it results in angina pectoris, myocardial stunning, myocardial hibernation, ischemic preconditioning, postconditioning, or under the most severe instances, acute coronary syndrome and myocardial...
" - 2002 H3(-/-) mice (mice that do not have this receptor)