Histamine H₃ receptors are expressed in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and to a lesser extent the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

, where they act as

autoreceptor An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the au ...

s in presynaptic

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...

rgic

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

s and control

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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neurot ...

(i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...

, GABA,

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

, noradrenaline,

and

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

. 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.Rapanelli, Maximiliano. “The Magnificent Two: Histamine and the H3 Receptor as Key Modulators of Striatal Circuitry.” ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 73 (February 2017): 36–40

Tissue distribution

Central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

Peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

Heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

Lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...

s *

Gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

Endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...

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 Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

. Also, the β and γ subunits interact with

N-type voltage gated calcium channels N-type calcium channels also called Cav2.2 channels are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells. The calcium N-channel consists of several subunits: the primar ...

, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H₃ receptors function as presynaptic

autoreceptors An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the a ...

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

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...

s 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.

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: * (''R'')-α-methylhistamine *

Cipralisant Cipralisant (GT-2331, tentative trade name Perceptin) is an extremely potent histamine H3 receptor ligand originally developed by Gliatech. Cipralisant was initially classified as a selective H3 antagonist, but newer research (2005) suggests a ...

(initially assessed as H₃ antagonist, later found to be an agonist, shows

functional selectivity Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...

, activating some G-protein coupled pathways but not others) * 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

These include: * A-304121 (No tolerance formation, silent antagonist) * A-349,821 * ABT-239 *

Betahistine Betahistine, sold under the brand name Serc among others, is an anti-vertigo medication. It is commonly prescribed for balance disorders or to alleviate vertigo symptoms. It was first registered in Europe in 1970 for the treatment of Ménière' ...

(also weak H₁ agonist) *

Burimamide Burimamide 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. Burimamide was first developed by scientists at ...

(also weak H₂ antagonist) * Ciproxifan * Clobenpropit (also H₄ antagonist) * Conessine * Failproxifan (No tolerance formation) * Impentamine * Iodophenpropit * Irdabisant * Pitolisant *

Thioperamide Thioperamide is a potent HRH4 antagonist and selective HRH3 antagonist capable of crossing the blood–brain barrier. It was used by Jean-Charles Schwartz in his early experiments regarding the H3 receptor. Thioperamide was found to be an ant ...

(also H₄ antagonist) * VUF-5681 (4- -(1H-Imidazol-4-yl)propyliperidine)

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.Sadek, Bassem, Ali Saad, Adel Sadeq, Fakhreya Jalal, and Holger Stark. “Histamine H3 Receptor as a Potential Target for Cognitive Symptoms in Neuropsychiatric Diseases.” ''Behavioural Brain Research'' 312 (October 2016): 415–430 Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions. This receptor has been proposed as a target for treating sleep disorders. The receptor has also been proposed as a target for treating neuropathic

pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...

. Because of its ability to modulate other neurotransmitters, H₃ receptor

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s are being investigated for the treatment of numerous neurological conditions, including

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

(because of the histamine/

orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...

ergic system interaction),

movement disorder Movement disorder refers to any clinical syndrome with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. Movement disorders are synonymous with basal ganglia or extrapyramidal ...

s (because of H₃ receptor-modulation of dopamine and GABA in the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

and

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(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 Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

and histamine).Sadek, Bassem, Ali Saad, Adel Sadeq, Fakhreya Jalal, and Holger Stark. “Histamine H3 Receptor as a Potential Target for Cognitive Symptoms in Neuropsychiatric Diseases.” ''Behavioural Brain Research'' 312 (October 2016): 415–430 There is also evidence that the H3-receptor plays an important role in

Tourette syndrome Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...

. Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms. The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.Baldan, Lissandra Castellan, Kyle A. Williams, Jean-Dominique Gallezot, Vladimir Pogorelov, Maximiliano Rapanelli, Michael Crowley, George M. Anderson, et al. “Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice.” Neuron 81, no. 1 (January 8, 2014): 77–90

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 Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

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)

References

External links

* * {{Histaminergics Histamine receptors