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 par ...

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 brain ...

, 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 aut ...

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 discovered in ...

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. N ...

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. Neur ...

(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 compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

, 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. Part ...

noradrenaline 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'', ...

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 vas ...

. 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 par ...

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 brain ...

Heart The heart is a muscular 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 carbon dioxide t ...

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 t ...

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 organ (biology), organs of the digestive syste ...

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 vessel ...

Function

Like all histamine receptors, the H₃ receptor is a

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...

. The H₃ receptor is coupled to the G_i

G-protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...

, 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 (biochemistry), receptor located in the cell membrane, membranes of neuron, nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or ...

on histamine-containing neurons. The diverse expression of H₃ receptors throughout the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

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 isof ...

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 al ...

(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 A-349,821 is a potent and selective Histamine H3 receptor, histamine H3 receptor Receptor antagonist, antagonist (or possibly an inverse agonist). It has nootropic effects in animal studies, although there do not appear to be any plans for clinic ...

* 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 (also weak H₂ antagonist) *

Ciproxifan Ciproxifan 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 ...

Clobenpropit Clobenpropit is a histamine H3 receptor antagonist. It has neuroprotective effects via stimulation of GABA release in brain cells ''in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, ...

(also H₄ antagonist) *

Conessine Conessine is a steroid alkaloid found in a number of plant species from the family Apocynaceae, including ''Holarrhena floribunda'', ''Holarrhena antidysenterica'' and ''Funtumia elastica''. It acts as a histamine antagonist, selective for the His ...

* Failproxifan (No tolerance formation) * Impentamine * Iodophenpropit * Irdabisant *

Pitolisant Pitolisant, sold under the brand name Wakix among others, is a medication for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is a histamine 3 (H3) receptor antagonist/inverse agonist. It represents the first commercia ...

Thioperamide Thioperamide is a potency (pharmacology), potent Histamine H4 receptor, HRH4 antagonist and binding selectivity, selective histamine H3 receptor, HRH3 receptor antagonist, antagonist capable of crossing the blood–brain barrier. It was used by Je ...

(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 disorder A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...

s. 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 electr ...

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 we ...

(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 d ...

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 extern ...

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 withdra ...

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-inapp ...

(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 syn ...

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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

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 Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

" * 2002 H₃^(-/-) mice (mice that do not have this receptor)

References

External links

* * {{Histaminergics Histamine receptors