The 5-HT₃ receptor belongs to the

Cys-loop superfamily The Cys-loop ligand-gated ion channel superfamily is composed of nicotinic acetylcholine, GABAA, GABAA-ρ, glycine, 5-HT3, and zinc-activated (ZAC) receptors. These receptors are composed of five protein subunits which form a pentameric arrange ...

ligand-gated ion channels Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

(LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or

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 ...

receptors) which are

G protein-coupled receptors 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 evolutionarily-related p ...

. This ion channel is

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

-selective and mediates neuronal depolarization and excitation within the

central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known as ...

and

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

nervous systems In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

. As with other ligand gated ion channels, the 5-HT₃ receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

(Na),

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

(K), and

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

(Ca) ions. Binding of the

neurotransmitter 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. Neuro ...

5-hydroxytryptamine (

) to the 5-HT₃ receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitizing, inward current is predominantly carried by

and

ions. 5-HT₃ receptors have a negligible permeability to

anions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

. They are most closely related by homology to the

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ne ...

Structure

The 5-HT₃ receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, which are all G-protein-coupled. A functional channel may be composed of five identical 5-HT_3A subunits (homopentameric) or a mixture of 5-HT_3A and one of the other four 5-HT_3B, 5-HT_3C, 5-HT_3D, or 5-HT_3E subunits (heteropentameric). It appears that only the 5-HT_3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT_3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT_3AC, 5-HT_3AD, 5-HT_3AE, and the homomeric 5-HT_3A receptor. N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking. Ionophore receptor

The subunits surround a central

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...

in a pseudo-symmetric manner (Fig.1). Each subunit comprises an

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

N-terminal domain which comprises the orthosteric ligand-binding site; a

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short

C-terminus (Fig.1). Whereas extracellular domain is the site of action of

agonists An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...

and

competitive antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of r ...

s, the

domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

Human and mouse genes

The genes encoding human 5-HT₃ receptors are located on chromosomes 11 (HTR3A, HTR3B) and 3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen from

gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. ...

s. The genes HTR3A and

HTR3B 5-hydroxytryptamine (serotonin) receptor 3B, also known as ''HTR3B'', is a human gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs ...

encode the 5-HT_3A and 5-HT_3B subunits and

HTR3C 5-hydroxytryptamine receptor 3C is a protein that in humans is encoded by the ''HTR3C'' gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channel ...

HTR3D 5-hydroxytryptamine receptor 3D is a protein that in humans is encoded by the ''HTR3D'' gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels ...

and

HTR3E 5-hydroxytryptamine receptor 3E is a protein that in humans is encoded by the ''HTR3E'' gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels ...

encode the 5-HT_3C, 5-HT_3D and 5-HT_3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The

pathophysiological Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is th ...

role for these additional subunits has yet to be identified. The human 5-HT_3A receptor gene is similar in structure to the mouse gene which has 9

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s and is spread over ~13 kb. Four of its

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

s are exactly in the same position as the introns in the homologous α7-acetylcholine receptor gene, clearly showing their evolutionary relationship. Structure_of_the_5HT3_gene_in_mouse

Expression. The 5-HT_3C, 5-HT_3D and 5-HT_3E genes tend to show peripherally restricted pattern of expression, with high levels in the gut. In human

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

and

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

, for example, 5-HT_3C and 5-HT_3E

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

might be greater than for 5-HT_3A and 5-HT_3B. Polymorphism. In patients treated with

chemotherapeutic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...

drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HTR3B receptor subunit could be used as

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

of antiemetic drug efficacy. CDNA structure of the mouse 5HT3 receptor protein

Tissue distribution

The 5-HT₃ receptor is expressed throughout the

and

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 ...

s and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT₃ receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons,

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...

, and hippocampus, and in ferret

visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...

. 5-HT₃ receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, but evidence is inconclusive.

Effects

When the receptor is activated to open the ion channel by

, the following effects are observed: * CNS: nausea and vomiting center in

brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

, anxiety, as well as anticonvulsant and pro-

nociceptive Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...

activity. * PNS: neuronal excitation (in autonomic, nociceptive neurons),

emesis Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteriti ...

Agonists

Agonists for the receptor include: *

Cereulide Cereulide is a toxin produced by some strains of ''Bacillus cereus''. It is a potent cytotoxin that destroys mitochondria. It also causes nausea and vomiting. Cereulide acts as ionophore with a high affinity to potassium cations. Exposure to cere ...

* 2-methyl-5-HT * Alpha-Methyltryptamine *

Bufotenin Bufotenin (5-HO-DMT, bufotenine) is a tryptamine derivative - more specifically, a DMT derivative - related to the neurotransmitter serotonin. It is an alkaloid found in some species of toads (especially the skin), mushrooms and plants. The na ...

* Chlorophenylbiguanide *

Ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

Ibogaine Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as ''Tabernanthe iboga'', ''Voacanga africana'', and ''Tabernaemontana undulata''. It is a psychedelic with dissociative properties. Prel ...

* Phenylbiguanide *

Quipazine Quipazine is a serotonergic drug of the piperazine group which is used in scientific research. It was originally intended as an antidepressant but never developed for medical use. Pharmacology Pharmacodynamics Quipazine is a serotonin reuptake ...

* RS-56812: Potent and selective 5-HT₃ partial agonist, 1000x selectivity over other serotonin receptors * SR-57227 *

Varenicline Varenicline (trade name Chantix and Champix) is a medication used for smoking cessation. Varenicline is also used for the treatment of dry eye disease. The most common side-effects include nausea (feeling sick), insomnia (difficulty sleeping), a ...

YM-31636 YM-31636 is a potent and selective 5-HT3 agonist. Systemic administration of YM-31636 increased the number of fecal pellets in rats, and improves colonic motility. It also increases colonic secretions, but not to the point of inducing diarrhea. ...

S 21007 S, or s, is the nineteenth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''ess'' (pronounced ), plural ''esses''. History ...

(SAR c.f. CGS-12066A)

Antagonists

Antagonists for the receptor (sorted by their respective therapeutic application) include: *

Antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

s **

AS-8112 AS-8112 is a synthetic compound that acts as a selective antagonist at the dopamine receptor subtypes D2 and D3, and the serotonin receptor 5-HT3. It has potent antiemetic An antiemetic is a drug that is effective against vomiting and ...

Granisetron Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the v ...

Ondansetron Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It is also effective for treating gastroenteritis. It can be given by ...

Tropisetron Tropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. It was patented in 1982 ...

, page 187. * Gastroprokinetics **

Alosetron Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only. It was patented in 1987 and approved for medical use in 2 ...

** Batanopride **

Metoclopramide Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...

(high doses) **

Renzapride Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors. Renzapride was being develo ...

Zacopride Zacopride is a potent Antagonist (pharmacology), antagonist at the 5-HT3 receptor, 5-HT3 Receptor (biochemistry), receptor and an agonist at the 5-HT4 receptor, 5-HT4 receptor. It has anxiolytic and nootropic effects in animal models, with the (' ...

** M1, the major active metabolite of

mosapride Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastroin ...

Antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

s **

Mianserin Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closely ...

Mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is o ...

Vortioxetine Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. It is taken by mouth. Common side e ...

Antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

s **

Clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...

Olanzapine Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is t ...

Quetiapine Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...

Antimalarials Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...

Quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...

Chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

** Mefloquine * Others ** 3-Tropanyl indole-3-carboxylate ** Cannabidiol (CBD) **

Delta-9-Tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC'' ...

Lamotrigine Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut synd ...

(

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

) **

Memantine Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...

(

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

medication) **

Menthol Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature and ...

Thujone Thujone () is a ketone and a monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone. Though it is best known as a chemical compound in the spirit absinthe, it is unlikely to be responsib ...

Positive Allosteric Modulators

These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist: *

Indole Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environmen ...

Derivatives ** 5-chloroindole *Small Organic

Anaesthetics An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

Chloroform Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...

Halothane Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful i ...

Isoflurane Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...

Discovery

Identification of the 5-HT₃ receptor did not take place until 1986, lacking selective pharmacological tools. However, with the discovery that the 5-HT₃ receptor plays a prominent role in

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

- and

radiotherapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...

-induced

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

, and the concomitant development of selective 5-HT₃ receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT₃ receptors in cell lines and native tissues quickly followed.

References

External links

* {{DEFAULTSORT:5-Ht3 Receptor Ion channels Serotonin receptors

Structure

Human and mouse genes

Tissue distribution

Effects

Agonists

Antagonists

Positive Allosteric Modulators

Discovery

See also

References

External links