The 5-HT₇ receptor is a member of the

GPCR 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 ...

superfamily of cell surface

receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...

and is activated by the

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

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

(5-hydroxytryptamine, 5-HT). The 5-HT₇ receptor is coupled to G_s (stimulates the production of the intracellular signaling molecule

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT₇ receptor is encoded by the ''HTR7''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, which in humans is transcribed into 3 different splice variants.

Function

When the 5-HT₇ receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory

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

G_s from the GPCR complex. G_s in turn activates

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

which increases

intracellular 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 ...

levels of the

second messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...

. The 5-HT₇ receptor plays a role in

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

relaxation within the

vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...

and in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

. The highest 5-HT₇ receptor densities are in the

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

and

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, and it is present at higher densities also in the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

and

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 ...

. The 5-HT₇ receptor is involved in

thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...

and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

, and

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

. Peripheral 5-HT₇ receptors are localized in enteric nerves; high levels of 5-HT₇ receptor-expressing mucosal nerve fibers were observed in the colon of patients with

irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

. An essential role of 5-HT₇ receptor in intestinal

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

was demonstrated in mouse models with

visceral hypersensitivity Visceral pain is defined as pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs) in the human body. Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, ...

, of which a novel 5-HT₇ receptor antagonist administered perorally reduced intestinal pain levels. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.

Variants

Three splice variants have been identified in humans (designated h5-HT_7(a), h5-HT_7(b), and h5-HT_7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT_7(a) is the full length receptor (445 amino acids), while the h5-HT_7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT_7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT_7(a). A 5-HT_7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT_7(d), as the rat 5-HT₇ gene lacks the exon necessary to encode this isoform. Drug binding affinities are similar across the three human splice variants; however, inverse agonist efficacies appear to differ between the splice variants.

Discovery

In 1983, evidence for a 5-HT₁-like receptor was first found. Ten years later, 5-HT₇ receptor was cloned and characterized. It has since become clear that the receptor described in 1983 is 5-HT₇.

Ligands

Numerous orthosteric ligands of moderate to high affinity are known. Signaling biased ligands were discovered and developed in 2018.

Agonists

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 ...

mimic the effects of the endogenous ligand, which is serotonin at the 5-HT₇ receptor (↑cAMP). * 5-Carboxamidotryptamine (5-CT) * 5-methoxytryptamine (5-MT, 5-MeOT) *

8-OH-DPAT 8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...

(mixed 5-HT_1A/5-HT₇ agonist) *

Aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

(weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

) * AS-19 *

E-55888 E-55888 is a drug developed by Esteve, which acts as a potent and selective full agonist at the 5HT7 serotonin receptor, and is used for investigating the role of 5-HT7 receptors in the perception of pain. When administered by itself, E-55888 i ...

* E-57431 *

LP-12 LP-12 is a drug which acts as a potent agonist at the 5HT7 serotonin receptor, with very high selectivity over other tested receptor subtypes such as the serotonin 5-HT1A and 5-HT2A, and the dopamine D2 receptor. It has been used to research the ...

(4-(2-Diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide) *

LP-44 LP-44 is a drug which acts as a potent and selective agonist at the 5HT7 serotonin receptor. While LP-44 is less selective than the related compound LP-12, it has been more widely used in research and has been used to show the complex role of 5- ...

(4- -(Methylthio)phenylN-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide) *

LP-211 LP-211 is a drug which acts as a potent and selective agonist at the 5HT7 serotonin receptor, with better brain penetration than older 5-HT7 agonists in the same series, and similar effects in animals. See also * AS-19 * E-55888 * LP-12 * LP-4 ...

* * MSD-5a * ''N_ω''-Methylserotonin * ''N''-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides (can function as either an agonist or antagonist depending on side chain substitution) *

N,N-Dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a serotonergic hallucinogen and investigational drug of the tryptamine family that occurs naturally in many plants and animals, including humans. ...

* AGH-107 (water-soluble, brain penetrating full agonist) * AH-494 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide) * AGH-192 (orally bioavailable, water-soluble, brain penetrating full agonist)

Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no

intrinsic activity Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind ...

but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT₇ receptor: ↓cAMP). Neutral antagonists and inverse agonists are typically referred to collectively as "antagonists" and, in the case of the 5-HT₇ receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT_7(a) and h5-HT_7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT_7(b) splice variant. * 3--3-ethyl-6-fluoro-1,3-dihydro-2''H''-indol-2-one *

Amisulpride Amisulpride, sold under the brand names Socian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prev ...

Amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...

Amoxapine Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylation, demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximat ...

Brexpiprazole Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and Agitation (dementia), agitation associated with dementia due to Alzhe ...

Clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...

Clozapine Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

* CYY1005 (a highly selective, orally active 5-HT7 antagonist) * DR-4485 * EGIS-12233 (mixed 5-HT₆/5-HT₇ antagonist) * AVN-101 (mixed 5-HT₆/5-HT₇ antagonist) *

Fluphenazine Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-pot ...

* Fluperlapine * ICI 169,369 *

Imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

* JNJ-18038683 *

Ketanserin Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...

* Loxapine * Lurasidone * LY-215,840 * Maprotiline * Mesulergine * Metitepine *

Methysergide Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from th ...

* Mianserin * Nuciferine *

Olanzapine Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomitin ...

Pimozide Pimozide (sold under the brand name Orap) is a neuroleptic medication, drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weigh ...

Pirepemat Pirepemat (; developmental code name IRL752 or IRL-752) is a drug which is under development for the prevention of falls in people with Parkinson's disease and Parkinson's disease dementia. It has been referred to as a " nootrope" (i.e., nootro ...

* RA-7 (1-(2-diphenyl)piperazine) *

Ritanserin Ritanserin, also known by its developmental code name R-55667, is a serotonin receptor antagonist, serotonin antagonist medication described as an anxiolytic, antidepressant, antiparkinsonian agent, and antihypertensive agent. It was chiefly inve ...

* SB-258,719 * SB-258741 * SB-269970 (highly 5-HT₇ selective) * SB-656104-A * SB-691673 *

Sertindole Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, ...

Spiperone Spiperone, also known as spiroperidol and sold under the brand name Spiropitan (( JP)) is a typical antipsychotic of the butyrophenone family related to haloperidol. It is approved for clinical use in Japan as a treatment for schizophrenia. Pha ...

* Tenilapine *

TFMPP 3-Trifluoromethylphenylpiperazine (TFMPP) is a recreational drug of the phenylpiperazine chemical class and is a substituted piperazine. Usually in combination with benzylpiperazine (BZP) and other structural analog, analogues, it is sold as an ...

* Vortioxetine * Trifluoperazine *

Ziprasidone Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The intramuscular form may be used for ...

* Zotepine

Tetrahydroisoquinoline Tetrahydroisoquinoline (TIQ or THIQ), also known as AMPH-CR, is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is mis ...

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

s found in

peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to glisten". p. ...

and related to

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

have been found to act as potent

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

s of the serotonin 5-HT₇ receptor. These compounds include pellotine, anhalidine, anhalonidine, anhalamine, and ''N''-methylanhalinine.

Inactivating antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitization. Inactivation of the 5-HT₇ receptor, however, does not arise from the classically described mechanisms of receptor desensitization via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization. Inactivating antagonists all likely interact with the 5-HT₇ receptor in an irreversible/pseudo-irreversible manner, as is the case with sup>3Hisperidone. *

Bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malig ...

Lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline family which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of l ...

Metergoline Metergoline (, ), also known as methergoline and sold under the brand names Contralac (veterinary) and Liserdol (clinical), is a monoaminergic medication of the ergoline group which is used as a prolactin inhibitor in the treatment of hyperprola ...

Methiothepin Metitepine (; developmental code names Ro 8-6837 (maleate), VUFB-6276 (mesylate)), also known as methiothepin, is a drug described as a " psychotropic agent" of the tricyclic or tetracyclic group which was never marketed. It acts as a non-sele ...

* Paliperidone *

Risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

References

External links

* * {{DEFAULTSORT:5-Ht7 Receptor Serotonin receptors