5-HT7 receptor
Encyclopedia
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors
and is activated by the neurotransmitter
serotonin
(5-hydroxytryptamine, 5-HT) The 5-HT7 receptor is coupled to Gs
(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 intron containing HTR7 gene
, which in humans is transcribed into 3 different splice variants.
(5-Hydroxytryptamine (5-HT)) plays an important role in various cognitive and behavioral functions. The serotonin receptor encoded by the HTR7 gene belongs to the superfamily of G protein-coupled receptor
s (GPCRs). When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein
Gs
from the GPCR complex. Gs in turn activates adenylate cyclase
which increases intracellular
levels of the second messenger
cAMP
.
The 5-HT7 receptor plays a role in smooth muscle
relaxation
within the vasculature and in the gastrointestinal tract
. The highest 5-HT7 receptor densities are in the thalamus
and hypothalamus
, and it is present at higher densities also in the hippocampus
and cortex
. The 5-HT7 receptor is involved in thermoregulation
, circadian rhythm
, learning
and memory
, and sleep
. 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.
have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT7(a) is the full length receptor (445 amino acids), while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(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-HT7(a). A 5-HT7(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-HT7(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.
disorder and other neuropsychiatric disorders.
to the 5-HT7 receptor with moderate to high affinity.
(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 inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
and is activated by the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-hydroxytryptamine, 5-HT) The 5-HT7 receptor is coupled to Gs
Heterotrimeric G protein
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and gamma subunits, the latter two referred to as the beta-gamma...
(stimulates the production of the intracellular signaling molecule cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
) 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 intron containing HTR7 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, which in humans is transcribed into 3 different splice variants.
Function
In humans, the neurotransmitter serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-Hydroxytryptamine (5-HT)) plays an important role in various cognitive and behavioral functions. The serotonin receptor encoded by the HTR7 gene belongs to the superfamily of G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s (GPCRs). When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein
Heterotrimeric G protein
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and gamma subunits, the latter two referred to as the beta-gamma...
Gs
Gs alpha subunit
The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:...
from the GPCR complex. Gs in turn activates adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
which increases intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
levels of the second messenger
Second messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
.
The 5-HT7 receptor plays a role in smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
relaxation
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
within the vasculature and in the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. The highest 5-HT7 receptor densities are in the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
and hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, and it is present at higher densities also in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
. The 5-HT7 receptor is involved in thermoregulation
Thermoregulation
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different...
, circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
, learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
, and sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
. It is also speculated that this receptor may be involved in mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....
regulation, suggesting that it may be a useful target in the treatment of depression.
Variants
Three splice variantsAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT7(a) is the full length receptor (445 amino acids), while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(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-HT7(a). A 5-HT7(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-HT7(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.Clinical signficance
This receptor gene is a candidate locus for involvement in autisticAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
disorder and other neuropsychiatric disorders.
Ligands
Numerous ligands bindBinding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
to the 5-HT7 receptor with moderate to high affinity.
Agonists
Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT7 receptor (↑cAMP).- 5-Carboxamidotryptamine5-Carboxamidotryptamine5-Carboxamidotryptamine 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 as at the 5-HT2, 5-HT3, 5-HT6 receptors with lower affinity. It has...
(5-CT) - 5-methoxytryptamine5-Methoxytryptamine5-Methoxytryptamine , 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 deacetylation of melatonin in the pineal gland.5-MT acts as a...
(5-MT, 5-MeOT) - 8-OH-DPAT8-OH-DPAT8-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...
(mixed 5-HT1A5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
/5-HT7 agonist) - AS-19AS-19 (drug)AS-19 is a substance which acts as a potent agonist at the 5HT7 receptor, with an IC50 of 0.83nM. It reverses the amnesia induced by drugs such as scopolamine and dizocilpine and improves long term memory acquisition, but inhibits short term memory formation....
- E-55888E-55888E-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...
- E-57431
- LP-12LP-12LP-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 involvement of the 5-HT7 receptor in as yet poorly...
(4-(2-Diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide) - LP-44LP-44LP-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-HT7 receptors in several aspects of brain function,...
(4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide) - LP-211LP-211LP-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....
- MSD-5a
- Nω-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)
- RA-71-(2-Diphenyl)piperazine1-piperazine, also known as RA-7, is a drug which acts as a potent and selective agonist at the 5HT7 serotonin receptor. It was discovered as an active metabolite of the synthetic 5-HT7 agonists LP-12 and LP-211, and unexpectedly turned out to be a similarly potent agonist with selectivity...
(1-(2-diphenyl)piperazine)
Antagonists
Neutral antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(also known as silent antagonists) bind the receptor and have no intrinsic activity
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
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 inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.
- 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one
- AmisulprideAmisulprideAmisulpride , is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder. In small doses it is also used to treat depression. It was introduced by Sanofi-Aventis in the 1990s.-Pharmacology:Amisulpride functions primarily as a D2 and D3 receptor...
- AmitriptylineAmitriptylineAmitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
- AmoxapineAmoxapineAmoxapine is a tetracyclic antidepressant of the dibenzoxazepine family, though it is often classified as a secondary amine tricyclic antidepressant.- Uses :...
- AripiprazoleAripiprazoleAripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
- ClomipramineClomipramineClomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
- ClozapineClozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
- CyproheptadineCyproheptadineCyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
- N,N-Dimethyltryptamine
- EGIS-12233EGIS-12233EGIS-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 dopamine release in cochlear tissue, suggesting a role for...
(mixed 5-HT6/5-HT7 antagonist) - FluphenazineFluphenazineFluphenazine is a typical antipsychotic drug used for the treatment of psychoses such as schizophrenia and acute manic phases of bipolar disorder. It belongs to the piperazine class of phenothiazines....
- FluperlapineFluperlapineFluperlapine , also known as fluoroperlapine, is a tricyclic atypical antipsychotic with additional antidepressant and sedative effects...
- ICI 169,369
- ImipramineImipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
- KetanserinKetanserinKetanserin is a drug with affinity for multiple G protein-coupled receptors . Initially it was believed to be a highly selective antagonist for serotonin 5-HT2A receptors, however this is not true. Ketanserin only has moderate selectivity for 5-HT2A receptors over 5-HT2C receptors...
- LoxapineLoxapineLoxapine is a typical antipsychotic medication, used primarily in the treatment of schizophrenia. It is a member of the dibenzoxazepine class and as a dibenzazepine derivative, it is structurally related to clozapine...
- LSDLSDLysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
- LY-215,840
- MaprotilineMaprotilineMaprotiline is a tetracyclic antidepressant . It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake....
- MesulergineMesulergineMesulergine is a psychoactive drug of the ergoline chemical class that acts on serotonin and dopamine receptors.The compound had entered clinical trials for the treatment of Parkinson's disease, however further development was halted due to adverse histological abnormalities in rats....
- MethysergideMethysergideMethysergide is a prescription drug used for prophylaxis of migraine headaches and is sold under the brand names Sansert and Deseril in 2 mg dosages.-Pharmacology:Methysergide interacts with serotonin receptors...
- MianserinMianserinMianserin is a psychoactive drug of the tetracyclic antidepressant chemical class which is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine effects...
- OlanzapineOlanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
- RitanserinRitanserinRitanserin is a serotonin antagonist with possibilities for the treatment of many neurological disorders.When used together with typical antipsychotics in the treatment of schizophrenia is able to decrease negative symptoms and adds some "atypicality" as parkinsonism is slightly decreased.-...
- SB-258,719SB-258,719SB-258,719 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...
- SB-258,741
- SB-269,970SB-269,970SB-269,970 is a drug and research chemical developed by GlaxoSmithKline used in scientific studies. It was previously believed to act as a selective 5-HT7 receptor antagonist , but a subsequent discovery showed that it also potently blocks the α2-adrenergic receptor...
(highly 5-HT7 selective) - SB-656,104-A
- SB-691,673
- SertindoleSertindoleSertindole is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of...
- SpiperoneSpiperoneSpiperone is a psychoactive drug and research chemical belonging to the butyrophenone chemical class. It functions as a 5-HT1A, 5-HT2A, 5-HT7, and D2 receptor antagonist, and has been used to identify these receptors when labeled with tritium. It has negligible affinity for the 5-HT2C receptor...
- SulpirideSulpirideSulpiride is an...
- Tenilapine
- TFMPP
- TrifluoperazineTrifluoperazineTrifluoperazine is a typical antipsychotic of the phenothiazine chemical class.- Uses :...
- ZiprasidoneZiprasidoneZiprasidone was the fifth atypical antipsychotic to gain FDA approval . In the United States, Ziprasidone is Food and Drug Administration approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients...
- ZotepineZotepineZotepine is an atypical antipsychotic indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 and Japan since 1982.- Pharmacology :...
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 [3H]risperidone.- BromocriptineBromocriptineBromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...
- LisurideLisurideLisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...
- MetergolineMetergolineMetergoline is a psychoactive drug of the ergoline chemical class which acts as a ligand for various serotonin and dopamine receptors....
- Methiothepin
- PaliperidonePaliperidonePaliperidone , also known as 9-hydroxyrisperidone, is an atypical antipsychotic developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing...
- RisperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...