5-HT2C receptor

5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled
Identifiers
Symbols HTR2C ; 5-HT1C; 5-HT2C; 5-HTR2C; 5HTR2C; HTR1C
External IDs OMIM: 312861 MGI: 96281 HomoloGene: 20242 IUPHAR: 8 ChEMBL: 225 GeneCards: HTR2C Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 3358 15560
Ensembl ENSG00000147246 ENSMUSG00000041380
UniProt P28335 P34968
RefSeq (mRNA) NM_000868 NM_008312
RefSeq (protein) NP_000859 NP_032338
Location (UCSC) Chr X:
114.58 – 114.91 Mb		 Chr X:
146.96 – 147.2 Mb
PubMed search

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,[1][2] 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.

Structure

At the cell surface the receptor exists as a homodimer.[3]

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 serotonin. Activation of this receptor by serotonin inhibits dopamine and norepinephrine release in certain areas of the brain.[4]

5-HT2C receptors are claimed to significantly regulate mood, anxiety, feeding, and reproductive behavior.[5] 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.[6] There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant.[7] Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Conversely, many SSRIs (but not fluoxetine, which is a 5-HT2C antagonist[8]) indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse although the delayed mood elevation that is usually typical of SSRIs is usually paralleled by the downregulation of the 5-HT2C receptors.[9] Many atypical antipsychotics 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.[8]

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 effects 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 agonists 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.[9] In addition to the evidence for a role of 5-HT2C receptor stimulation in depressive symptoms there also is evidence that activation of 5-HT2C receptors may have beneficial effects upon certain aspects of depression, one group of researchers found that direct stimulation of 5-HT2C receptors with a 5-HT2C agonist reduced cognitive deficits in mice with a TPH2 loss-of-function mutation.[10]

5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs,[11][12] 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 of 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.[13] However, chronic SSRI treatment may increase 5-HT2C expression, specifically in the choroid plexus.[14]

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 .

Endocrinology

Serotonin is involved in basal and stress-induced regulation of hypothalamus and pituitary gland hormones such as prolactin, adrenocorticotropic hormone (ACTH), vasopressin and oxytocin, mainly via actions of receptor subtypes 5-HT2A and 5-HT2C.[15] As such, the 5-HT2C receptor is a significant modulator of the hypothalamic–pituitary–adrenal axis (HPA axis).[16] 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 produce 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.[17]

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 SNORD115, the deletion of which is associated with Prader–Willi syndrome.[18][19] 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
Antagonists
Inverse Agonists
Partial Agonists

Interactions

The 5-HT2C receptor has been shown to interact with MPDZ.[22][23]

RNA editing

5HT2CR pre-mRNA can be the subject of RNA editing.[24] It is the only serotonin receptor as well as the only member 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 deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines 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.

Location

Editing occurs in 5 different closely located sites within exon 5, which 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. Thirty-two different mRNA variants can occur leading to 24 different protein isoforms.

  1. An Isoleucine to Valine (I/V) at amino acid position 157,161.
  2. An Isoleucine to a Methionine(I/M) at amino acid position 157
  3. An Aspartate to a Serine (N/S)at 159
  4. An Aspartate to Aspargine(N/D) at 159
  5. 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.[25] Another editing site, site F has also been located in the exon complementary sequence (ECS) of intron 5.[26] The ECS required for formation of double stranded RNA structure is found within intron 5.[24]

Conservation

RNA editing of this receptor occurs at 4 locations in the rat.[24] Editing also occurs in the mouse.[27] The initial demonstration of RNA editing in rat.[24] The predominant isoform in rat brain is VNV which differs from the most common type found in humans.[24][28] The editing complementary sequence is known to be conserved across Mammalia.

Regulation

The 5-HT2c receptor is the only serotonin receptor edited despite its close sequence similarities to other family members.[28] 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.[24] The different 5HT2CR mRNA isoforms are expressed differently throughout 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.[25][28][29]

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.[30][31][32] 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.[30] 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.[33] 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.[30][33] 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 codon 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 affect the affinity of the receptor for G protein binding.[24]

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.[24][28]

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.[34]

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 are 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.[26][29] Dysregulation

Serotonin family of receptors are often linked to pathology of several human mental conditions such as Schizophrenia, anxiety, Bipolar disorder and major depression.[35] 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.[36] Interestingly some studies have noted that there is an increase in RNA editing at site A in depressed suicide victims.[6][36] E site editing was observed to be increased in individuals suffering from major depression.[37] 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.[38][39]

See also

References

  1. ↑ "Entrez Gene: HTR2C 5-hydroxytryptamine (serotonin) receptor 2C".
  2. ↑ Stam NJ, Vanderheyden P, van Alebeek C, Klomp J, de Boer T, van Delft AM, Olijve W (November 1994). "Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor". Eur. J. Pharmacol. 269 (3): 339–48. doi:10.1016/0922-4106(94)90042-6. PMID 7895773.
  3. ↑ Herrick-Davis K, Grinde E, Lindsley T, Cowan A, Mazurkiewicz JE (2012). "Oligomer size of the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor revealed by fluorescence correlation spectroscopy with photon counting histogram analysis: evidence for homodimers without monomers or tetramers". J. Biol. Chem. 287 (28): 23604–14. doi:10.1074/jbc.M112.350249. PMC 3390635. PMID 22593582.
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  5. ↑ Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (July 2007). "Serotonin 5-HT2C receptors regulate anxiety-like behavior". Genes, Brain and Behavior 6 (5): 491–6. doi:10.1111/j.1601-183X.2007.00316.x. PMID 17451451.
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  7. ↑ Eser D, Baghai TC, Möller HJ (2010). "Agomelatine: The evidence for its place in the treatment of depression". Core Evid 4: 171–9. doi:10.2147/CE.S6005. PMC 2899775. PMID 20694073.
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  17. ↑ Birzniece V, Johansson IM, Wang MD, Bäckström T, Olsson T (February 2002). "Ovarian hormone effects on 5-hydroxytryptamine(2A) and 5-hydroxytryptamine(2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats". Neurosci. Lett. 319 (3): 157–61. doi:10.1016/S0304-3940(01)02570-8. PMID 11834317.
  18. ↑ Kishore S, Stamm S (January 2006). "The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C". Science 311 (5758): 230–2. Bibcode:2006Sci...311..230K. doi:10.1126/science.1118265. PMID 16357227.
  19. ↑ Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL (2008). "Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster.". Nat Genet 40 (6): 719–21. doi:10.1038/ng.158. PMC 2705197. PMID 18500341.
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  24. 1 2 3 4 5 6 7 8 Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (May 1997). "Regulation of serotonin-2C receptor G-protein coupling by RNA editing". Nature 387 (6630): 303–8. Bibcode:1997Natur.387..303B. doi:10.1038/387303a0. PMID 9153397.
  25. 1 2 Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR (August 1999). "Messenger RNA editing of the human serotonin 5-HT2C receptor". Neuropsychopharmacology 21 (2 Suppl): 82S–90S. doi:10.1016/S0893-133X(99)00004-4. PMID 10432493.
  26. 1 2 Flomen R, Knight J, Sham P, Kerwin R, Makoff A (2004). "Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene". Nucleic Acids Res. 32 (7): 2113–22. doi:10.1093/nar/gkh536. PMC 407821. PMID 15087490.
  27. ↑ Hackler EA, Airey DC, Shannon CC, Sodhi MS, Sanders-Bush E (May 2006). "5-HT(2C) receptor RNA editing in the amygdala of C57BL/6J, DBA/2J, and BALB/cJ mice". Neurosci. Res. 55 (1): 96–104. doi:10.1016/j.neures.2006.02.005. PMID 16580757.
  28. 1 2 3 4 Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (April 1999). "RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity". J. Biol. Chem. 274 (14): 9472–8. doi:10.1074/jbc.274.14.9472. PMID 10092629.
  29. 1 2 Wang Q, O'Brien PJ, Chen CX, Cho DS, Murray JM, Nishikura K (March 2000). "Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin2C receptors". J. Neurochem. 74 (3): 1290–300. doi:10.1046/j.1471-4159.2000.741290.x. PMID 10693963.
  30. 1 2 3 Yang W, Wang Q, Kanes SJ, Murray JM, Nishikura K (April 2004). "Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy". Brain Res. Mol. Brain Res. 124 (1): 70–8. doi:10.1016/j.molbrainres.2004.02.010. PMID 15093687.
  31. ↑ Sukma M, Tohda M, Watanabe H, Matsumoto K (August 2005). "The mRNA expression differences of RNA editing enzymes in differentiated and undifferentiated NG108-15 cells". J. Pharmacol. Sci. 98 (4): 467–70. doi:10.1254/jphs.SC0050074. PMID 16082172.
  32. ↑ Tohda M, Sukma M, Watanabe H (October 2004). "RNA editing and short variant of serotonin 2C receptor mRNA in neuronally differentiated NG108-15 cells". J. Pharmacol. Sci. 96 (2): 164–9. doi:10.1254/jphs.FP0040227. PMID 15492466.
  33. 1 2 Hartner JC, Schmittwolf C, Kispert A, Müller AM, Higuchi M, Seeburg PH (February 2004). "Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1". J. Biol. Chem. 279 (6): 4894–902. doi:10.1074/jbc.M311347200. PMID 14615479.
  34. ↑ Marion S, Weiner DM, Caron MG (January 2004). "RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms". J. Biol. Chem. 279 (4): 2945–54. doi:10.1074/jbc.M308742200. PMID 14602721.
  35. ↑ Baxter G, Kennett G, Blaney F, Blackburn T (March 1995). "5-HT2 receptor subtypes: a family re-united?". Trends Pharmacol. Sci. 16 (3): 105–10. doi:10.1016/S0165-6147(00)88991-9. PMID 7792930.
  36. 1 2 Iwamoto K, Kato T (August 2003). "RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders". Neurosci. Lett. 346 (3): 169–72. doi:10.1016/S0304-3940(03)00608-6. PMID 12853111.
  37. ↑ Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C (April 2002). "Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims". Neuron 34 (3): 349–56. doi:10.1016/S0896-6273(02)00660-8. PMID 11988167.
  38. ↑ Iwamoto K, Nakatani N, Bundo M, Yoshikawa T, Kato T (September 2005). "Altered RNA editing of serotonin 2C receptor in a rat model of depression". Neurosci. Res. 53 (1): 69–76. doi:10.1016/j.neures.2005.06.001. PMID 16005997.
  39. ↑ Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C (December 2002). "Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission". J. Neurosci. 22 (24): 10529–32. PMID 12486144.

Further reading

  • Niswender CM, Sanders-Bush E, Emeson RB (1999). "Identification and characterization of RNA editing events within the 5-HT2C receptor.". Ann. N. Y. Acad. Sci. 861 (1 ADVANCES IN S): 38–48. Bibcode:1998NYASA.861...38N. doi:10.1111/j.1749-6632.1998.tb10171.x. PMID 9928237. 
  • Hoyer D, Hannon JP, Martin GR (2002). "Molecular, pharmacological and functional diversity of 5-HT receptors.". Pharmacol. Biochem. Behav. 71 (4): 533–54. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546. 
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