5-HT2C receptor
Encyclopedia
The 5-HT2C receptor is a subtype of 5-HT receptor
that binds the endogenous
neurotransmitter
serotonin
(5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor
(GPCR) that is coupled to Gq/G11
and mediates excitatory neurotransmission
. HTR2C denotes the human
gene
encoding for the receptor
, that in humans is located at the X chromosome. As males have one copy of the gene and in females one of the two copies of the gene is repressed, polymorphisms at this receptor can affect the two sexes to differing extent.
. Activation of this receptor by serotonin inhibits dopamine
and norepinephrine
release in certain areas of the brain.
5-HT2C receptors significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in the striatum
, prefrontal cortex
, nucleus accumbens
, hippocampus
, hypothalamus
, and amygdala
, among others.
Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT2C antagonist
, is an effective antidepressant
. Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Conversely, fluoxetine
and other SSRIs
indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse
. Many atypical antipsychotic
s block 5-HT2C receptors, but their clinical use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake
, however, the clinical significance of this action is variable.
An overactivity of 5-HT2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT2C by serotonin is responsible for many of the negative side effect
s of SSRI and SNRI medications, such as sertraline
, paroxetine
, venlafaxine
, and others. Some of the initial anxiety caused by SSRIs is due to excessive signalling at 5-HT2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT2A, 5-HT1A, and other serotonin receptors. This downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy. Thus, 5-HT2C receptors do not require binding by a ligand
(serotonin) in order to exhibit influence on neurotransmission. Inverse agonist
s may be required to fully extinguish 5-HT2C constitutive activity, and may prove useful in the treatment of 5-HT2C-mediated conditions in the absence of typical serotonin activity.
5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine
, nicotine
, amphetamine
, morphine
, cocaine
, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, and many dopaminergic stimuli. Feeding, social interaction, and sexual activity all release dopamine subject to inhibition by 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli.
Many GPCRs downregulate in response to agonists for the receptor, and upregulate in response to antagonists. The 5-HT2A and 5-HT2C receptors appear to downregulate in response to both antagonists and agonists. Chronic treatment with antipsychotic drugs, which possess 5-HT2 antagonist activity, results in downregulation of both 5-HT2A and 5-HT2C, as does chronic treatment with SSRIs and other 5-HT agonists. However, chronic SSRI treatment may increase 5-HT2C expression, specifically in the choroid plexus.
Conditions that increase cytokine
levels in the human body may have potential to raise 5-HT2C gene expression in the brain. This could possibly comprise a link between viral infections and associated depression. Cytokine therapy has been shown to increase 5-HT2C gene expression, resulting in increased activity of 5-HT2C receptors in the brain.
, adrenocorticotropic hormone (ACTH), vasopressin
and oxytocin
, mainly via actions of receptor subtypes 5-HT2A and 5-HT2C. As such, the 5-HT2C receptor is a significant modulator of Hypothalamic–pituitary–adrenal axis (HPA axis). The HPA axis is the main controller of acute sympathetic
stress responses related to fight-or-flight response
. Prolonged activation and disturbances of the HPA axis contribute to depressive and anxiety symptoms seen in many psychopathological conditions.
Stimulation of 5-HT2C receptors leads to increase of corticotropin releasing hormone (CRH) and vasopressin mRNA in the paraventricular nucleus
and proopiomelanocortin in the anterior pituitary lobe. In rats, restraint stress (which can produces depressive symptoms if being chronic) induces secretion of prolactin, ACTH, vasopressin and oxytocin which is partially mediated via 5-HT2C receptor. Responses during such conditions as dehydration or haemorrhage causes the release oxytocin via serotonergic response that is partly mediated via 5-HT2C. In addition, peripheral release of vasopressin involves serotonergic response which is partially mediated via 5-HT2C.
Expression of the 5-HT2C receptor in the CNS is modulated by female sex hormones estradiol
and progesterone
. Combination of the hormones decrease the receptor concentration in the ventral hippocampus
in rats and could thus affect mood.
, the deletion of which is associated with Prader–Willi syndrome. As the human gene is located in the X chromosome, males have only one copy of the gene whereas women have two, meaning that mutations in the gene affect the phenotype of men even when the allele would be recessive in nature. As women have two copies of the gene, but only one allele is expressed in each cell, they are a mosaic for polymorphisms, meaning that one genetic variant may be prevalent in one tissue and another variant will be prevalent in a different tissue (as with all other x-linked genetic variations).
Antagonists
Inverse Agonists
with MPDZ
.
. It is the only serotonin receptor as well as being the one of the large family of 7 transmembrane receptors (7TMRs) known to be edited. Different levels of editing result in a variety of effects on receptor function.
A to I RNA editing is catalyzed by a family of adenosine deaminase
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine
. Inosine
s are recognised as guanosine
by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1
and ADAR2
being the only enzymatically active members. ADAR3
is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
ADARs bind interact directly with the dsRNA substrate via their double stranded RNA binding domains. If an editing site occurs within a coding sequence, it can result in a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore editing can also alter protein function. A to I editing occurs in a non coding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs ( especially Alu repeats) The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
These codon changes which can occur due to A to I editing at these sites can lead to a maximum of 32 different mRNA variants leading to 24 different protein isoforms. The number of protein isoforms is less than 32 since some amino acids are encoded by more than one codon. Another editing site , site F has also been located in the exon complementary sequence (ECS) of intron 5. The ECS required for formation of double stranded RNA structure is found within intron 5.
Mice knock out and other studies have been used to determine which ADAR enzyme are involved in editing. Editing at A and B sites has been demonstrated to be due to ADAR1 editing. Also since ADAR1 expression is increased in response to the presence of interferon α, it was also observed that editing at A and B sites was also increased because of this. C' and D sites require ADAR2 and editing is decreased by the presence of ADAR1 with editing of C' site only observed in ADAR1 double knock out mice. The C site has been shown to be mainly edited by ADAR2 but in presence of upregulated expression of ADAR1 , there was an increase in editing of this site and the enzymes presence can also result in limited editing in ADAR 2 knock out mice. This demonstrates that there must be some form interaction between the two A to I editing enzymes. Also such interactions and tissue specific expression of ADARs interaction may explain the variety in editing patterns in different regions of the brain.
Structure
As mentioned editing results in several codaon changes.The editing sites are found in the second intracellular domain of the protein which is also the receptors G protein coupling domain.Therefore editing of these sites can effect the affinity of the receptor for G protein binding.
Function
Editing results in reduced affinity for specific G proteins which in turn affects internal signalling via second messengers (Phospholipase C signalling system). The fully edited isoform, VGV, considerably reduces 5-HT potency, G-protein coupling and agonist binding, compared to the unedited protein isoform , INI. 72-76. Most evidence for the effect of editing on function comes from downstream measurements of receptor activity , radio ligand binding and functional studies.Inhibitory effects are linked to the extent of editing.Those isoforms with a higher level of editing require higher levels of serotonin to activate the phospholipase c pathway. Unedited INI form has a greater tendency to isomerise to an active form which can more easily interact with G proteins. This indicates that RNA editing here may be a mechanism for regulating neuronal excitability by stabilising receptor signalling.
Editing is also thought to function in cell surface expression of the receptor subtype.The fully edited VGV which has the lowest level of constitutive activity is fully expressed at the cell surface while the non edited INI is internalised and accumulates in endosome.
Editing is also thought to influence splicing.Three different spliced isoforms of the receptor exist .Editing regulates the amount of 5HT2CR mRNA which leads to translation of the full length protein selection of alternative splice sites. t76,77. These splice sites termed Gu1, Gu2 , GU3.Only GU2 site splicing results in translation of the full length receptor while editing at GU1 is known to result in translation of a truncated protein.This is thought to be a regulatory mechanism to decrease the amount of unedited isoform INI to limit serotonin response when editing is inefficient. Most of the pre-mRNAs which are edited are spliced at the GU2 site.
Dysregulation
Serotonin family of receptors are often linked to pathology of several human mental conditions such as Schizophrenia , anxiety, Bipolar disorder and major depression. There have been several experimental investigations into the effects of alternative editing patterns of the 5HT2CR and these conditions with a wide variability in results especially those relating to schizophrenia. Interestingly some studies have noted that there is an increase in in RNA editing at site A in depressed suicide victims. E site editing was observed to be increased in individuals suffering from major depression. In rat models this increase is also observed and can be reversed with fluoxetine with some suggestion that E site editing maybe linked to major depression.
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
that binds the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
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). It is a 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...
(GPCR) that is coupled to Gq/G11
Gq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
and mediates excitatory neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
. HTR2C denotes the human
Human
Humans are the only living species in the Homo genus...
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...
encoding for the receptor
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...
, that in humans is located at the X chromosome. As males have one copy of the gene and in females one of the two copies of the gene is repressed, polymorphisms at this receptor can affect the two sexes to differing extent.
Distribution
5-HT2C receptors are widely distributed across the periphery and brain in humans.Function
The 5-HT2C receptor is one of the many binding sites for 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...
. Activation of this receptor by serotonin inhibits dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
release in certain areas of the brain.
5-HT2C receptors significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
, nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
, 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...
, hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, and amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, among others.
Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT2C antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
, is an effective antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
. Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Conversely, fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
and other SSRIs
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. Many atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s block 5-HT2C receptors, but their clinical use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
, however, the clinical significance of this action is variable.
An overactivity of 5-HT2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT2C by serotonin is responsible for many of the negative side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s of SSRI and SNRI medications, such as sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
, paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, and others. Some of the initial anxiety caused by SSRIs is due to excessive signalling at 5-HT2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT2A, 5-HT1A, and other serotonin receptors. This downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy. Thus, 5-HT2C receptors do not require binding by a ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
(serotonin) in order to exhibit influence on neurotransmission. Inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
s may be required to fully extinguish 5-HT2C constitutive activity, and may prove useful in the treatment of 5-HT2C-mediated conditions in the absence of typical serotonin activity.
5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
, amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, and many dopaminergic stimuli. Feeding, social interaction, and sexual activity all release dopamine subject to inhibition by 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli.
Many GPCRs downregulate in response to agonists for the receptor, and upregulate in response to antagonists. The 5-HT2A and 5-HT2C receptors appear to downregulate in response to both antagonists and agonists. Chronic treatment with antipsychotic drugs, which possess 5-HT2 antagonist activity, results in downregulation of both 5-HT2A and 5-HT2C, as does chronic treatment with SSRIs and other 5-HT agonists. However, chronic SSRI treatment may increase 5-HT2C expression, specifically in the choroid plexus.
Conditions that increase cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
levels in the human body may have potential to raise 5-HT2C gene expression in the brain. This could possibly comprise a link between viral infections and associated depression. Cytokine therapy has been shown to increase 5-HT2C gene expression, resulting in increased activity of 5-HT2C receptors in the brain.
Endocrinology
Serotonin is involved in basal and stress-induced regulation of hypothalamus and pituitary gland hormones such as prolactinProlactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, adrenocorticotropic hormone (ACTH), vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
and oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
, mainly via actions of receptor subtypes 5-HT2A and 5-HT2C. As such, the 5-HT2C receptor is a significant modulator of Hypothalamic–pituitary–adrenal axis (HPA axis). The HPA axis is the main controller of acute sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
stress responses related to fight-or-flight response
Fight-or-flight response
The fight-or-flight response was first described by Walter Bradford Cannon....
. Prolonged activation and disturbances of the HPA axis contribute to depressive and anxiety symptoms seen in many psychopathological conditions.
Stimulation of 5-HT2C receptors leads to increase of corticotropin releasing hormone (CRH) and vasopressin mRNA in the paraventricular nucleus
Paraventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
and proopiomelanocortin in the anterior pituitary lobe. In rats, restraint stress (which can produces depressive symptoms if being chronic) induces secretion of prolactin, ACTH, vasopressin and oxytocin which is partially mediated via 5-HT2C receptor. Responses during such conditions as dehydration or haemorrhage causes the release oxytocin via serotonergic response that is partly mediated via 5-HT2C. In addition, peripheral release of vasopressin involves serotonergic response which is partially mediated via 5-HT2C.
Expression of the 5-HT2C receptor in the CNS is modulated by female sex hormones estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
. Combination of the hormones decrease the receptor concentration in the ventral 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...
in rats and could thus affect mood.
Genetics
Many human polymorphisms have been identified influencing the expression of 5-HT2C. Significant correlations are suggested, specifically in relation to psychiatric disorders such as depression, OCD, and anxiety-related conditions. Polymorphisms also correlate with susceptibility to a number of conditions including drug abuse and obesity. There are indications that the alternative splicing of the 5-HT2C receptor is regulated by a snoRNA called SNORD115Small nucleolar RNA SNORD115
SNORD115 is a non-coding RNA molecule known as a small nucleoloar RNA which usually functions in guiding the modification of other non-coding RNAs. This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
, the deletion of which is associated with Prader–Willi syndrome. As the human gene is located in the X chromosome, males have only one copy of the gene whereas women have two, meaning that mutations in the gene affect the phenotype of men even when the allele would be recessive in nature. As women have two copies of the gene, but only one allele is expressed in each cell, they are a mosaic for polymorphisms, meaning that one genetic variant may be prevalent in one tissue and another variant will be prevalent in a different tissue (as with all other x-linked genetic variations).
Ligands
Agonists- A-372,159A-372,159A-372,159 is a drug which acts as a potent and selective partial agonist for the 5HT2C receptor, with more than 100x selectivity over the closely related 5-HT2B receptor and a Ki of 3nM. It has been found to produce anorectic effects in animal studies and produced significant weight loss in rats...
- AL-38022AAL-38022AAL-38022A is an indazole derivative drug which is one of a range of similar drugs developed for scientific research and with some possible clinical applications. It acts as a potent and selective agonist for the 5-HT2 family of serotonin receptors, with highest binding affinity for the 5-HT2C...
- AripiprazoleAripiprazoleAripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
- CP-809,101CP-809,101CP-809,101 is a drug which acts as a potent and selective 5-HT2C receptor agonist. It had promising results in animal models of obesity and psychosis, but associated with genotoxicity which means that future use will be restricted to scientific research applications only....
- FenfluramineFenfluramineFenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
- 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...
- LorcaserinLorcaserinLorcaserin is a weight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application was submitted to the Food and Drug Administration in the United States and lorcaserin is pending approval...
- 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....
- MK-212
- NaphthylisopropylamineNaphthylisopropylamineNaphthylisopropylamine is an experimental drug currently under investigation for the treatment of alcohol and stimulant addiction....
- NorfenfluramineNorfenfluramineNorfenfluramine is a psychoactive drug which functions as a serotonin releasing agent and potent 5HT2B receptor agonist. The action of norfenfluramine on 5HT2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the...
- Org 12,962Org 12,962Org 12,962 is a drug developed by Organon, which acts as a potent and selective agonist for the 5-HT2 receptor family, with highest affinity at 5-HT2C and lowest at 5-HT2B subtypes...
- ORG-37,684ORG-37,684Org 37,684 is a drug developed by Organon, which acts as a potent and selective agonist for the 5-HT2 receptor family, with highest affinity at 5-HT2C and lowest at 5-HT2B subtypes. It has anorectic effects in animal studies and has been researched as a potential weight loss drug for use in humans....
- OxaflozaneOxaflozaneOxaflozane is an antidepressant and anxiolytic drug that was introduced in France in 1982 by Solvay for the treatment of depression, but has since been abandoned. It is a prodrug to N-dealkyloxaflozane, which acts as a non-selective serotonin receptor agonist for the 5-HT1A , 5-HT2A , and 5-HT2C ...
- PNU-22394PNU-22394PNU-22394 is a drug which acts as an agonist at serotonin 5-HT2 receptors, with strongest binding affinity for 5-HT2A and 5-HT2C and slightly weaker at 5-HT2B, although it is only a full agonist at 5-HT2C, but partial agonist at 5-HT2A and 5-HT2B. It has anorectic effects in both animal studies and...
- PsychedelicPsychedelic drugA psychedelic substance is a psychoactive drug whose primary action is to alter cognition and perception. Psychedelics are part of a wider class of psychoactive drugs known as hallucinogens, a class that also includes related substances such as dissociatives and deliriants...
s- Lysergamides (LSD, etc.)
- PhenethylamineSubstituted phenethylamineThe substituted phenethylamines are chemical compounds with the 2-phenethylamine chemical structure modified at the phenyl ring, sidechain, and/or amino group. Some of them are psychoactive drugs, including stimulants, psychedelics, opioids, and entactogens, which exert their effects primarily...
s (2C-B, DOI2,5-Dimethoxy-4-iodoamphetamine2,5-dimethoxy-4-iodoamphetamine is a psychedelic drug and a substituted amphetamine of the phenethylamine family. It is also a powerful anti-inflammatory that is effective at doses on the order of 100 micrograms in humans, far below its effective dose as a psychedelic. Despite being a substituted...
, DOM2,5-Dimethoxy-4-methylamphetamine2,5-Dimethoxy-4-methylamphetamine is a psychedelic and a substituted amphetamine...
, MescalineMescalineMescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class used mainly as an entheogen....
, etc.) - PiperazinePiperazinePiperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
s (mCPP, TFMPP, etc.) - TryptamineTryptamineTryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
s (5-MeO-DMT5-MeO-DMT5-MeO-DMT is a powerful psychedelic tryptamine. It is found in a wide variety of plant and psychoactive toad species and, like its close relatives DMT and bufotenin , it has been used as an entheogen by South American shamans for thousands of years.-Chemistry:5-MeO-DMT was first synthesized in...
, BufoteninBufoteninBufotenin , or 5-hydroxy-dimethyltryptamine , is a tryptamine related to the neurotransmitter serotonin...
, DMTDimethyltryptamineN,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
, PsilocinPsilocinPsilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...
, etc.)
- Ro60-0175Ro60-0175Ro60-0175 is a drug developed by Hoffmann–La Roche, which has applications in scientific research. It acts as a potent and selective agonist for both the 5-HT2B and 5-HT2C serotonin receptor subtypes, with good selectivity over the closely related 5-HT2A subtype, and little or no affinity at other...
- VabicaserinVabicaserinVabicaserin was a novel antipsychotic and anorectic under development by Wyeth. As of 2010 it is no longer in clinical trials for the treatment of psychosis...
- WAY-629
- WAY-161,503
- YM-348YM-348YM-348 is an indazole derivative drug which acts as a potent and selective 5-HT2C receptor agonist, with an EC50 of 1nM and 15x selectivity over 5-HT2A, although it only has moderate selectivity of 3x over the closely related 5-HT2B receptor. It has thermogenic and anorectic effects in animal...
Antagonists
- Agomelatine
- EltoprazineEltoprazineEltoprazine is a drug of the phenylpiperazine class which is a serenic or antiaggressive agent. It acts as an agonist at the 5-HT1A and 5-HT1B receptors and as an antagonist at the 5-HT2C receptor. It is closely related to fluprazine and batoprazine, which are similarly acting drugs....
- EtoperidoneEtoperidoneEtoperidone , also known as clopradone and thozalinone, is an antidepressant of the phenylpiperazine class which was introduced in Europe in 1977...
- FluoxetineFluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
- FR-260,010
- Lu AA24530Lu AA24530Tedatioxetine is a antidepressant currently under development by Lundbeck and Takeda for the treatment of major depressive disorder . As of March 2010 it is in phase III clinical trials...
- 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...
- NefazodoneNefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
- NorfluoxetineNorfluoxetineSeproxetine, also known as -norfluoxetine, is a selective serotonin reuptake inhibitor . It is an active metabolite of fluoxetine. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant but development was never completed and the drug was never marketed.-Synthesis:Fuller,...
- O-DesmethyltramadolO-DesmethyltramadolO-Desmethyltramadol is an opioid analgesic and the main active metabolite of tramadol.-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed...
- RS-102,221RS-102,221RS-102,221 is a drug developed by Hoffmann–La Roche, which was one of the first compounds discovered that acts as a potent and selective antagonist at the serotonin 5-HT2C receptor, with around 100x selectivity over the closely related 5-HT2A and 5-HT2B receptors...
- SB-200,646
- SB-221,284
- SB-242,084SB-242,084SB-242,084 is a psychoactive drug and research chemical which acts as a selective antagonist for the 5HT2C receptor. It has anxiolytic effects, and enhances dopamine signalling in the limbic system, as well as having complex effects on the dopamine release produced by cocaine, increasing it in some...
- SDZ SER-082SDZ SER-082SDZ SER-082 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors, with good selectivity over other serotonin receptor subtypes and slight preference for 5-HT2C over 5-HT2B. It has been used in animal studies into the behavioural effects of the different 5-HT2...
- TramadolTramadolTramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
- TrazodoneTrazodoneTrazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
Inverse Agonists
- AntidepressantAntidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s- TricyclicTricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (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...
, 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 :...
, ImipramineImipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, NortriptylineNortriptylineNortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
, etc.) - TetracyclicTetracyclic antidepressantTetracyclic antidepressants are a class of drugs used primarily as antidepressants that were first introduced in the 1970s. They are named after their chemical structure which contains four rings of atoms and are closely related to the tricyclic antidepressants which contain three rings of...
s (MirtazapineMirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
, 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...
, AmoxapineAmoxapineAmoxapine is a tetracyclic antidepressant of the dibenzoxazepine family, though it is often classified as a secondary amine tricyclic antidepressant.- Uses :...
, etc.)
- Tricyclic
- AntihistamineAntihistamineAn H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s (CyproheptadineCyproheptadineCyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
, HydroxyzineHydroxyzineHydroxyzine is a first-generation antihistamine of the diphenylmethane and piperazine classes. It was first synthesized by Union Chimique Belge in 1956 and was marketed by Pfizer in the United States later the same year, and is still in widespread use today....
, Latrepirdine, etc.) - AntipsychoticAntipsychoticAn antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s- TypicalTypical antipsychoticTypical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
s (ChlorpromazineChlorpromazineChlorpromazine is a typical antipsychotic...
, 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....
, 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...
, ThioridazineThioridazineThioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
, etc.) - AtypicalAtypical antipsychoticThe atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s (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...
, OlanzapineOlanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, QuetiapineQuetiapineQuetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
, 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...
, 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...
, etc.)
- Typical
- CinanserinCinanserinCinanserin is a 5-HT2A and 5-HT2C receptor antagonist which was discovered in the 1960s.The preparation is effective against an atypical pneumonia ....
- DeramciclaneDeramciclaneDeramciclane is a drug which acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor....
- 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...
- LY-53,857
- MetergolineMetergolineMetergoline is a psychoactive drug of the ergoline chemical class which acts as a ligand for various serotonin and dopamine receptors....
- Methiothepin
- PizotifenPizotifenPizotifen or pizotyline , trade name Sandomigran, is a benzocycloheptene based drug used as a medicine, primarily as a preventative to reduce the frequency of recurrent migraine headaches.-Uses:...
- 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-206,553SB-206,553SB-206,553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors....
- SB-228,357
- SB-243,213
- SB-242,084SB-242,084SB-242,084 is a psychoactive drug and research chemical which acts as a selective antagonist for the 5HT2C receptor. It has anxiolytic effects, and enhances dopamine signalling in the limbic system, as well as having complex effects on the dopamine release produced by cocaine, increasing it in some...
Interactions
The 5-HT2C receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with MPDZ
MPDZ
Multiple PDZ domain protein is a protein that in humans is encoded by the MPDZ gene.-Interactions:MPDZ has been shown to interact with CD117, PLEKHA1 and 5-HT2C receptor.-Further reading:...
.
RNA editing
5HT2CR pre-mRNA can be the subject of RNA editingRNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
. It is the only serotonin receptor as well as being the one of the large family of 7 transmembrane receptors (7TMRs) known to be edited. Different levels of editing result in a variety of effects on receptor function.
Type
The type of RNA editing that occurs in the pre-mRNA of the 5HT2CR is Adenosine to Inosine ( A to I) editing.A to I RNA editing is catalyzed by a family of adenosine deaminase
Adenosine deaminase
Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:...
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
. Inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
s are recognised as guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1
ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
and ADAR2
ADARB1
Double-stranded RNA-specific editase 1 is an enzyme that in humans is encoded by the ADARB1 gene.ADAR2 requires the small molecule inositol hexakisphosphate for proper function.-Further reading:...
being the only enzymatically active members. ADAR3
ADARB2
Double-stranded RNA-specific editase B2 is an enzyme that in humans is encoded by the ADARB2 gene.-Further reading:...
is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
ADARs bind interact directly with the dsRNA substrate via their double stranded RNA binding domains. If an editing site occurs within a coding sequence, it can result in a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore editing can also alter protein function. A to I editing occurs in a non coding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs ( especially Alu repeats) The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
Location
Editing occurs in 5 different closely located sites within exon 5 which is corresponds to the second intracellular loop of the final protein. The sites are known as A, B, C′ (previously called E), C and D and are predicted to occur within amino acid positions 156, 158 and 160. Several codon changes can occur due to A to I editing at these sites.32 different mRNA variants can occur leading to 24 different protein isoforms.- An Isoleucine to Valine (I/V) at amino acid position 157,161.
- An Isoleucine to a Methionine(I/M) at amino acid position 157
- An Aspartate to a Serine (N/S)at 159
- An Aspartate to Aspargine(N/D) at 159
- An Asparagine to a Glycine(N/G) at 159.
These codon changes which can occur due to A to I editing at these sites can lead to a maximum of 32 different mRNA variants leading to 24 different protein isoforms. The number of protein isoforms is less than 32 since some amino acids are encoded by more than one codon. Another editing site , site F has also been located in the exon complementary sequence (ECS) of intron 5. The ECS required for formation of double stranded RNA structure is found within intron 5.
Conservation
RNA editing of this receptor occurs at 4 locations in the rat. Editing also occurs in the mouse. The initial demonstration of RNA editing in rat. The predominant isoform in rat brain is VNV which differs from the most common type found in humans. The editing complementary sequence is known to be conserved across Mammalia.Regulation
5HT2c receptor is the only serotonin receptor edited despite its close sequence similarities to other family members. 5HT2CR is different due to possessing an imperfect inverted repeat at the end of exon 5 and the beginning of intron 5 allowing formation of an RNA duplex producing the dsRNA required by ADARs for editing. Disruption of this inverted repeat was demonstrated to cease all editing. The different 5HT2CR mRNA isoforms are expressed differently throughourt the brain, yet not all of the 24 have been detected perhaps due to tissue specific expression or low frequency editing of a particular type. Those isoforms that are not expressed at all or at a very low frequency are linked by being edited only at site C' and/or site B but not at site A. Some examples of differences in frequency of editing and site edited in different parts of the human brain of 5HT2CR include low frequency of editing in cerebellum and nearly all editing is at site D while in the hippocampus editing frequency is higher with site A being the main editing site. Site C' is only found edited in the thalamus. The most common isoform in human brain is the VSV isoform.Mice knock out and other studies have been used to determine which ADAR enzyme are involved in editing. Editing at A and B sites has been demonstrated to be due to ADAR1 editing. Also since ADAR1 expression is increased in response to the presence of interferon α, it was also observed that editing at A and B sites was also increased because of this. C' and D sites require ADAR2 and editing is decreased by the presence of ADAR1 with editing of C' site only observed in ADAR1 double knock out mice. The C site has been shown to be mainly edited by ADAR2 but in presence of upregulated expression of ADAR1 , there was an increase in editing of this site and the enzymes presence can also result in limited editing in ADAR 2 knock out mice. This demonstrates that there must be some form interaction between the two A to I editing enzymes. Also such interactions and tissue specific expression of ADARs interaction may explain the variety in editing patterns in different regions of the brain.
Consequences
Second, the editing pattern controls the amount of the 5-HT2CR mRNA that leads to the expression of full-length protein through the modulation of alternative splice site selection 76,77. Among three alternative splice donor sites (GU1 to GU3; Fig. 4C), GU2 is the only site that forms the mature mRNA to produce the functional, full-length 5-HT2CR protein. Unedited pre-mRNAs tend to be spliced at the GU1 site, resulting in the truncated, non-functional protein if translated 76,77. However, most pre-mRNAs edited at more than one position are spliced at GU2 77. Thus, when editing is inefficient, increased splicing at GU1 may act as a control mechanism to decrease biosynthesis of the 5-HT2CR-INI and thereby limit serotonin response. Third, RNA editing controls the ultimate physiological output of constitutively active receptors by affecting the cell surface expression of the 5-HT2CR. The 5-HT2CR-VGV, which displays the lowest level of constitutive activity, is fully expressed at the cell surface under basal conditions and is rapidly internalized in the presence of agonist 78. In contrast, the 5-HT2CR-INI is constitutively internalized and accumulates in endosomes 78.Structure
As mentioned editing results in several codaon changes.The editing sites are found in the second intracellular domain of the protein which is also the receptors G protein coupling domain.Therefore editing of these sites can effect the affinity of the receptor for G protein binding.
Function
Editing results in reduced affinity for specific G proteins which in turn affects internal signalling via second messengers (Phospholipase C signalling system). The fully edited isoform, VGV, considerably reduces 5-HT potency, G-protein coupling and agonist binding, compared to the unedited protein isoform , INI. 72-76. Most evidence for the effect of editing on function comes from downstream measurements of receptor activity , radio ligand binding and functional studies.Inhibitory effects are linked to the extent of editing.Those isoforms with a higher level of editing require higher levels of serotonin to activate the phospholipase c pathway. Unedited INI form has a greater tendency to isomerise to an active form which can more easily interact with G proteins. This indicates that RNA editing here may be a mechanism for regulating neuronal excitability by stabilising receptor signalling.
Editing is also thought to function in cell surface expression of the receptor subtype.The fully edited VGV which has the lowest level of constitutive activity is fully expressed at the cell surface while the non edited INI is internalised and accumulates in endosome.
Editing is also thought to influence splicing.Three different spliced isoforms of the receptor exist .Editing regulates the amount of 5HT2CR mRNA which leads to translation of the full length protein selection of alternative splice sites. t76,77. These splice sites termed Gu1, Gu2 , GU3.Only GU2 site splicing results in translation of the full length receptor while editing at GU1 is known to result in translation of a truncated protein.This is thought to be a regulatory mechanism to decrease the amount of unedited isoform INI to limit serotonin response when editing is inefficient. Most of the pre-mRNAs which are edited are spliced at the GU2 site.
Dysregulation
Serotonin family of receptors are often linked to pathology of several human mental conditions such as Schizophrenia , anxiety, Bipolar disorder and major depression. There have been several experimental investigations into the effects of alternative editing patterns of the 5HT2CR and these conditions with a wide variability in results especially those relating to schizophrenia. Interestingly some studies have noted that there is an increase in in RNA editing at site A in depressed suicide victims. E site editing was observed to be increased in individuals suffering from major depression. In rat models this increase is also observed and can be reversed with fluoxetine with some suggestion that E site editing maybe linked to major depression.
See also
- 5-HT receptor5-HT receptorThe serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
- 5-HT2 receptor5-HT2 receptorThe 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...
- Anxiety/Aggression-Driven DepressionAnxiety/aggression-driven depressionAnxiety/aggression-driven depression is a subtype of depression first proposed by the Dutch psychiatrist Herman M. van Praag in 1996...