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 p ...

superfamily of cell surface receptors and is activated by 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. Neur ...

serotonin (5-hydroxytryptamine, 5-HT) The 5-HT₇ receptor is coupled to G_s (stimulates the production of the intracellular signaling molecule cAMP) 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 (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

, 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 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 ...

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 or cell signaling, encompassing both first m ...

cAMP. The 5-HT₇ receptor plays a role in

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

relaxation within the

vasculature The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

and in the

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 a ...

. The highest 5-HT₇ receptor densities are in the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direction ...

and

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

, and it is present at higher densities also in the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

and cortex. 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, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

, learning 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 remembered ...

, and

sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...

. 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 "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms ma ...

. An essential role of 5-HT₇ receptor in intestinal

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

was demonstrated in mouse models with visceral hypersensitivity, 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 Mood may refer to: *Mood (psychology), a relatively long lasting emotional state Music *The Mood, a British pop band from 1981 to 1984 * Mood (band), hip hop artists * ''Mood'' (Jacquees album), 2016 * ''Moods'' (Barbara Mandrell album), 1978 ...

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 agoni ...

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

5-Carboxamidotryptamine 5-Carboxamidotryptamine (5-CT) is a tryptamine derivative closely related to the neurotransmitter serotonin. 5-CT acts as a non-selective, high-affinity full agonist at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A, and 5-HT7 receptors, as well a ...

(5-CT) *

5-methoxytryptamine 5-Methoxytryptamine (5-MT), also known as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin. 5-MT has been shown to occur naturally in the body in low levels. It is biosynthesized via the deacet ...

(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. It was one of the first major 5-HT1A receptor full agonists to be disco ...

(mixed 5-HT_1A/5-HT₇ agonist) *

Aripiprazole Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depress ...

(weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...

) * 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 ...

* 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 t ...

(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)phenyl The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as s ...

N-(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- ...

* 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 ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...

* 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 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 is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold un ...

* Amitriptyline * Amoxapine *

Brexpiprazole Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by t ...

* Clomipramine *

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 resp ...

* CYY1005 (a highly selective, orally active 5-HT7 antagonist) *

DR-4485 DR-4485 is a compound which acts as a potent and selective antagonist for the 5-HT7 receptor, with good oral bioavailability. It has been used to research the function of this still comparatively little studied serotonin receptor subtype. Refe ...

EGIS-12233 EGIS-12,233 is a drug with applications in scientific research, acting as a potent and selective antagonist for both the 5-HT6 and 5-HT7 serotonin receptor subtypes, with good selectivity over other receptors. It has been shown to increase ...

(mixed 5-HT₆/5-HT₇ antagonist) * AVN-101 (mixed 5-HT₆/5-HT₇ antagonist) * Fluphenazine *

Fluperlapine Fluperlapine (NB 106-689), also known as fluoroperlapine, is a morphanthridine (11''H''-dibenzo ,ezepine) atypical antipsychotic with additional antidepressant and sedative effects. It was first synthesized in 1979, and then subsequently studi ...

ICI 169,369 ICI or Ici may refer to: Companies and organisations * ICI Homes, builder, Florida. US * Former UK Imperial Chemical Industries ** ICI Australia, later Orica * Independent Curators International, New York City, US * Indian Concrete Institute * ...

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. The drug is also used to treat bedwetting. ...

JNJ-18038683 JNJ-18038683 is a potent and selective antagonist of the 5HT7 serotonin receptor discovered by Johnson & Johnson. It has nootropic and antidepressant effects in both animal and human studies and has progressed to Phase II trials as an adjunct ...

* Ketanserin * Loxapine * Lurasidone *

LY-215,840 LY-215,840 is an ergoline derivative drug developed by Eli Lilly, which acts as a potent and selective antagonist at the serotonin 5-HT2 and 5-HT7 receptors. It has anti-hypertensive Hypertension (HTN or HT), also known as high blood pr ...

Maprotiline Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary ...

* Mesulergine * Methysergide *

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 close ...

* Olanzapine * Pimozide * RA-7 (1-(2-diphenyl)piperazine) * Ritanserin *

SB-258,719 SB-258719 is a drug developed by GlaxoSmithKline which acts as a selective 5-HT7 receptor partial inverse agonist, and was the first such ligand identified for 5-HT7. Its use in research has mainly been in demonstrating the potential use for 5- ...

* SB-258741 * SB-269970 (highly 5-HT₇ selective) * SB-656104-A * SB-691673 * Sertindole * Spiperone *

Tenilapine Tenilapine is an atypical antipsychotic which has never been marketed in the US. Pharmacodynamics Tenilapine has a relatively high affinity for the 5-HT2A receptor, and relatively low (micromolar) affinities for dopamine receptors. The ratio ...

* TFMPP *

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 ...

* Trifluoperazine * Ziprasidone * Zotepine

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 mali ...

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

* Metergoline *

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 group which was never marketed. It acts as a non-selective antagonis ...

* Paliperidone * Risperidone

References

External links

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