The activity of the serotonin receptor 2C is regulated by alternative splicing

Abstract

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is decreased by pre-mRNA editing as well as alternative pre-mRNA splicing, which generates a truncated isoform that switches off 5HT2C receptor activity through heterodimerization; showing that RNA processing regulates the constitutive activity of the 5HT2C system. RNA processing events influencing the constitutive activity target exon Vb that forms a stable double stranded RNA structure with its downstream intron. This structure can be targeted by small molecules and oligonucleotides that change exon Vb alternative splicing and influence 5HT2C signaling in mouse models, leading to a reduction in food intake. Thus, the 5HT2C system is a candidate for RNA therapy in multiple models of CNS disorders.

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References

  1. Barbon A, Orlandi C, La Via L, Caracciolo L, Tardito D, Musazzi L, Mallei A, Gennarelli M, Racagni G, Popoli M, Barlati S (2011) Antidepressant treatments change 5-HT2C receptor mRNA expression in rat prefrontal/frontal cortex and hippocampus. Neuropsychobiology 63:160–168. doi:10.1159/000321593

    CAS  Article  PubMed  Google Scholar 

  2. Becamel C, Gavarini S, Chanrion B, Alonso G, Galeotti N, Dumuis A, Bockaert J, Marin P (2004) The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J Biol Chem 279:20257–20266. doi:10.1074/jbc.M312106200

    CAS  Article  PubMed  Google Scholar 

  3. Bennett DJ, Gorassini M, Fouad K, Sanelli L, Han Y, Cheng J (1999) Spasticity in rats with sacral spinal cord injury. J Neurotrauma 16:69–84

    CAS  Article  PubMed  Google Scholar 

  4. Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54:94–104

    CAS  PubMed  Google Scholar 

  5. Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP (2001) RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol 134:386–392. doi:10.1038/sj.bjp.0704255

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK (2014) Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Investig 124:1868. doi:10.1172/JCI75669

    CAS  Article  PubMed Central  Google Scholar 

  7. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308. doi:10.1038/387303a0

    CAS  Article  PubMed  Google Scholar 

  8. Carlin KP, Jiang Z, Brownstone RM (2000) Characterization of calcium currents in functionally mature mouse spinal motoneurons. Eur J Neurosci 12:1624–1634

    CAS  Article  PubMed  Google Scholar 

  9. Carlsson A, Magnusson T, Rosengren E (1963) 5-Hydroxytryptamine of the spinal cord normally and after transection. Experientia 19:359

    CAS  Article  PubMed  Google Scholar 

  10. Carmel L, Koonin EV, Dracheva S (2012) Dependencies among editing sites in serotonin 2C receptor mRNA. PLoS Comput Biol 8:e1002663. doi:10.1371/journal.pcbi.1002663

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Castensson A, Emilsson L, Sundberg R, Jazin E (2003) Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis. Biol Psychiatry 54:1212–1221

    CAS  Article  PubMed  Google Scholar 

  12. Castensson A, Aberg K, McCarthy S, Saetre P, Andersson B, Jazin E (2005) Serotonin receptor 2C (HTR2C) and schizophrenia: examination of possible medication and genetic influences on expression levels. Am J Med Genet B Neuropsychiatr Genet 134B:84–89. doi:10.1002/ajmg.b.30151

    Article  PubMed  Google Scholar 

  13. Cavaille J (2017) Box C/D small nucleolar RNA genes and the Prader–Willi syndrome: a complex interplay. Wiley Interdiscip Rev RNA. doi:10.1002/wrna.1417

    PubMed  Google Scholar 

  14. Chagraoui A, Thibaut F, Skiba M, Thuillez C, Bourin M (2016) 5-HT2C receptors in psychiatric disorders: a review. Prog Neuropsychopharmacol Biol Psychiatry 66:120–135. doi:10.1016/j.pnpbp.2015.12.006

    CAS  Article  PubMed  Google Scholar 

  15. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578. doi:10.1038/nn1455

    CAS  Article  PubMed  Google Scholar 

  16. Deffit SN, Hundley HA (2016) To edit or not to edit: regulation of ADAR editing specificity and efficiency. Wiley Interdiscip Rev RNA 7:113–127. doi:10.1002/wrna.1319

    CAS  Article  PubMed  Google Scholar 

  17. Di Narzo AF, Kozlenkov A, Roussos P, Hao K, Hurd Y, Lewis DA, Sibille E, Siever LJ, Koonin E, Dracheva S (2014) A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum Mol Genet 23:4801–4813. doi:10.1093/hmg/ddu195

    Article  PubMed  PubMed Central  Google Scholar 

  18. Di Narzo AF, Kozlenkov A, Ge Y, Zhang B, Sanelli L, May Z, Li Y, Fouad K, Cardozo C, Koonin EV, Bennett DJ, Dracheva S (2015) Decrease of mRNA editing after spinal cord injury is caused by down-regulation of ADAR2 that is triggered by inflammatory response. Sci Rep 5:12615. doi:10.1038/srep12615

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dracheva S, Chin B, Haroutunian V (2008) Altered serotonin 2C receptor RNA splicing in suicide: association with editing. NeuroReport 19:379–382. doi:10.1097/WNR.0b013e3282f556d2

    CAS  Article  PubMed  Google Scholar 

  20. Driscoll DJ, Miller JL, Schwartz S, Cassidy SB (1993–2017) Prader–Willi Syndrome. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA

  21. Du Y, Stasko M, Costa AC, Davisson MT, Gardiner KJ (2007) Editing of the serotonin 2C receptor pre-mRNA: effects of the Morris Water Maze. Gene 391:186–197. doi:10.1016/j.gene.2006.12.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Falaleeva M, Welden JR, Duncan MC, Stamm S (2017) C/D-box snoRNAs form methylating and non methylating ribonucleoprotein complexes: old dogs show new tricks. Bioessays. doi:10.1002/bies.201600264 (in press)

    PubMed  Google Scholar 

  23. 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 32:2113–2122

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Fouad K, Rank MM, Vavrek R, Murray KC, Sanelli L, Bennett DJ (2010) Locomotion after spinal cord injury depends on constitutive activity in serotonin receptors. J Neurophysiol 104:2975–2984. doi:10.1152/jn.00499.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Fukuda M, Oyama Y, Nishitarumizu A, Omura M, Nose K, Deshimaru M (2015) Identification of an RNA element for specific coordination of A-to-I RNA editing on HTR2C pre-mRNA. Genes Cells 20:834–846. doi:10.1111/gtc.12272

    CAS  Article  PubMed  Google Scholar 

  26. Garfield AS, Davies JR, Burke LK, Furby HV, Wilkinson LS, Heisler LK, Isles AR (2016) Increased alternate splicing of Htr2c in a mouse model for Prader–Willi syndrome leads disruption of 5HT2C receptor mediated appetite. Mol Brain 9:95. doi:10.1186/s13041-016-0277-4

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gorassini MA, Knash ME, Harvey PJ, Bennett DJ, Yang JF (2004) Role of motoneurons in the generation of muscle spasms after spinal cord injury. Brain 127:2247–2258. doi:10.1093/brain/awh243

    Article  PubMed  Google Scholar 

  28. Greenway FL, Shanahan W, Fain R, Ma T, Rubino D (2016) Safety and tolerability review of lorcaserin in clinical trials. Clin Obes 6:285–295. doi:10.1111/cob.12159

    CAS  Article  PubMed  Google Scholar 

  29. Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C (2002a) Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission. J Neurosci 22:10529–10532

    CAS  PubMed  Google Scholar 

  30. Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C (2002b) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34:349–356

    CAS  Article  PubMed  Google Scholar 

  31. Hartner JC, Schmittwolf C, Kispert A, Muller AM, Higuchi M, Seeburg PH (2004) Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem 279:4894–4902. doi:10.1074/jbc.M311347200

    CAS  Article  PubMed  Google Scholar 

  32. Harvey PJ, Li X, Li Y, Bennett DJ (2006a) 5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury. J Neurophysiol 96:1158–1170. doi:10.1152/jn.01088.2005

    CAS  Article  PubMed  Google Scholar 

  33. Harvey PJ, Li Y, Li X, Bennett DJ (2006b) Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult rats. J Neurophysiol 96:1141–1157. doi:10.1152/jn.00335.2005

    CAS  Article  PubMed  Google Scholar 

  34. Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (2007) Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav 6:491–496. doi:10.1111/j.1601-183X.2007.00316.x

    CAS  Article  PubMed  Google Scholar 

  35. Herrick-Davis K (2013) Functional significance of serotonin receptor dimerization. Exp Brain Res 230:375–386. doi:10.1007/s00221-013-3622-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Herrick-Davis K, Grinde E, Niswender CM (1999) Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. J Neurochem 73:1711–1717

    CAS  Article  PubMed  Google Scholar 

  37. Herrick-Davis K, Grinde E, Mazurkiewicz JE (2004) Biochemical and biophysical characterization of serotonin 5-HT2C receptor homodimers on the plasma membrane of living cells. Biochemistry 43:13963–13971. doi:10.1021/bi048398p

    CAS  Article  PubMed  Google Scholar 

  38. Herrick-Davis K, Weaver BA, Grinde E, Mazurkiewicz JE (2006) Serotonin 5-HT2C receptor homodimer biogenesis in the endoplasmic reticulum: real-time visualization with confocal fluorescence resonance energy transfer. J Biol Chem 281:27109–27116. doi:10.1074/jbc.M604390200

    CAS  Article  PubMed  Google Scholar 

  39. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O (1988) Bistability of alpha-motoneurones in the decerebrate cat and in the acute spinal cat after intravenous 5-hydroxytryptophan. J Physiol 405:345–367

    Article  PubMed  PubMed Central  Google Scholar 

  40. Humphrey PP, Hartig P, Hoyer D (1993) A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 14:233–236

    CAS  Article  PubMed  Google Scholar 

  41. Jacobs BL, Martin-Cora FJ, Fornal CA (2002) Activity of medullary serotonergic neurons in freely moving animals. Brain Res Brain Res Rev 40:45–52

    CAS  Article  PubMed  Google Scholar 

  42. Jorjani H, Kehr S, Jedlinski DJ, Gumienny R, Hertel J, Stadler PF, Zavolan M, Gruber AR (2016) An updated human snoRNAome. Nucleic Acids Res 44:5068–5082. doi:10.1093/nar/gkw386

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Karanovic J, Svikovic S, Pantovic M, Durica S, Brajuskovic G, Damjanovic A, Jovanovic V, Ivkovic M, Romac S, Savic Pavicevic D (2015) Joint effect of ADARB1 gene, HTR2C gene and stressful life events on suicide attempt risk in patients with major psychiatric disorders. World J Biol Psychiatry 16:261–271. doi:10.3109/15622975.2014.1000374

    Article  PubMed  Google Scholar 

  44. Kim D, Murray M, Simansky KJ (2001) The serotonergic 5-HT(2C) agonist m-chlorophenylpiperazine increases weight-supported locomotion without development of tolerance in rats with spinal transections. Exp Neurol 169:496–500. doi:10.1006/exnr.2001.7660

    CAS  Article  PubMed  Google Scholar 

  45. Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311:230–232

    CAS  Article  PubMed  Google Scholar 

  46. Kishore S, Khanna A, Zhang Z, Hui J, Balwierz PJ, Stefan M, Beach C, Nicholls RD, Zavolan M, Stamm S (2010) The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 19:1153–1164. doi:10.1093/hmg/ddp585

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Li Y, Gorassini MA, Bennett DJ (2004) Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats. J Neurophysiol 91:767–783. doi:10.1152/jn.00788.2003

    CAS  Article  PubMed  Google Scholar 

  48. Li X, Murray K, Harvey PJ, Ballou EW, Bennett DJ (2007) Serotonin facilitates a persistent calcium current in motoneurons of rats with and without chronic spinal cord injury. J Neurophysiol 97:1236–1246. doi:10.1152/jn.00995.2006

    CAS  Article  PubMed  Google Scholar 

  49. Macbeth MR, Schubert HL, Vandemark AP, Lingam AT, Hill CP, Bass BL (2005) Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309:1534–1539. doi:10.1126/science.1113150

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Mancia F, Assur Z, Herman AG, Siegel R, Hendrickson WA (2008) Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep 9:363–369. doi:10.1038/embor.2008.27

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Marcucci R, Brindle J, Paro S, Casadio A, Hempel S, Morrice N, Bisso A, Keegan LP, Del Sal G, O’Connell MA (2011) Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J 30:4211–4222. doi:10.1038/emboj.2011.303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Martin CB, Ramond F, Farrington DT, Aguiar AS Jr, Chevarin C, Berthiau AS, Caussanel S, Lanfumey L, Herrick-Davis K, Hamon M, Madjar JJ, Mongeau R (2013) RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice. Mol Psychiatry 18:656–665. doi:10.1038/mp.2012.171

    CAS  Article  PubMed  Google Scholar 

  53. Martin CB, Hamon M, Lanfumey L, Mongeau R (2014) Controversies on the role of 5-HT(2C) receptors in the mechanisms of action of antidepressant drugs. Neurosci Biobehav Rev 42:208–223. doi:10.1016/j.neubiorev.2014.03.001

    CAS  Article  PubMed  Google Scholar 

  54. McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150:129–142. doi:10.1016/j.pharmthera.2015.01.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Mickey BJ, Sanford BJ, Love TM, Shen PH, Hodgkinson CA, Stohler CS, Goldman D, Zubieta JK (2012) Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans. J Neurosci 32:9344–9350. doi:10.1523/JNEUROSCI.1260-12.2012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Mongeau R, Martin CB, Chevarin C, Maldonado R, Hamon M, Robledo P, Lanfumey L (2010) 5-HT2C receptor activation prevents stress-induced enhancement of brain 5-HT turnover and extracellular levels in the mouse brain: modulation by chronic paroxetine treatment. J Neurochem 115:438–449. doi:10.1111/j.1471-4159.2010.06932.x

    CAS  Article  PubMed  Google Scholar 

  57. Monti JM (2011) Serotonin control of sleep-wake behavior. Sleep Med Rev 15:269–281. doi:10.1016/j.smrv.2010.11.003

    Article  PubMed  Google Scholar 

  58. Morabito MV, Abbas AI, Hood JL, Kesterson RA, Jacobs MM, Kump DS, Hachey DL, Roth BL, Emeson RB (2010) Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader–Willi Syndrome. Neurobiol Dis 39:169–180

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Murray KC, Nakae A, Stephens MJ, Rank M, D’Amico J, Harvey PJ, Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K (2010) Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med 16:694–700. doi:10.1038/nm.2160

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Nakae A, Nakai K, Tanaka T, Hosokawa K, Mashimo T (2013) Serotonin 2C receptor alternative splicing in a spinal cord injury model. Neurosci Lett 532:49–54. doi:10.1016/j.neulet.2012.10.034

    CAS  Article  PubMed  Google Scholar 

  61. Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K, Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T (2009) Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137:1235–1246

    Article  PubMed  PubMed Central  Google Scholar 

  62. Navarrett S, Collier L, Cardozo C, Dracheva S (2012) Alterations of serotonin 2C and 2A receptors in response to T10 spinal cord transection in rats. Neurosci Lett 506:74–78. doi:10.1016/j.neulet.2011.10.052

    CAS  Article  PubMed  Google Scholar 

  63. Nielsen JB, Crone C, Hultborn H (2007) The spinal pathophysiology of spasticity—from a basic science point of view. Acta Physiol 189:171–180. doi:10.1111/j.1748-1716.2006.01652.x

    CAS  Article  Google Scholar 

  64. Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472–9478

    CAS  Article  PubMed  Google Scholar 

  65. Ottesen EW (2017) ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy. Transl Neurosci 8:1–6. doi:10.1515/tnsci-2017-0001

    Article  PubMed  PubMed Central  Google Scholar 

  66. Perrier JF, Delgado-Lezama R (2005) Synaptic release of serotonin induced by stimulation of the raphe nucleus promotes plateau potentials in spinal motoneurons of the adult turtle. J Neurosci 25:7993–7999. doi:10.1523/JNEUROSCI.1957-05.2005

    CAS  Article  PubMed  Google Scholar 

  67. Rabchevsky AG, Kitzman PH (2011) Latest approaches for the treatment of spasticity and autonomic dysreflexia in chronic spinal cord injury. Neurother J Am Soc Exp NeuroTher 8:274–282. doi:10.1007/s13311-011-0025-5

    CAS  Article  Google Scholar 

  68. Rabchevsky AG, Patel SP, Lyttle TS, Eldahan KC, O’Dell CR, Zhang Y, Popovich PG, Kitzman PH, Donohue KD (2012) Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. Front Physiol 3:329. doi:10.3389/fphys.2012.00329

    Article  PubMed  PubMed Central  Google Scholar 

  69. Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL (2000) Synaptic control of motoneuronal excitability. Physiol Rev 80:767–852

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ren LQ, Wienecke J, Chen M, Moller M, Hultborn H, Zhang M (2013) The time course of serotonin 2C receptor expression after spinal transection of rats: an immunohistochemical study. Neuroscience 236:31–46. doi:10.1016/j.neuroscience.2012.12.063

    CAS  Article  PubMed  Google Scholar 

  71. Rodriguez EM, Blazquez JL, Guerra M (2010) The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides 31:757–776. doi:10.1016/j.peptides.2010.01.003

    CAS  Article  PubMed  Google Scholar 

  72. Schellekens H, Clarke G, Jeffery IB, Dinan TG, Cryan JF (2012) Dynamic 5-HT2C receptor editing in a mouse model of obesity. PLoS One 7:e32266. doi:10.1371/journal.pone.0032266

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Schellekens H, van Oeffelen WE, Dinan TG, Cryan JF (2013) Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288:181–191. doi:10.1074/jbc.M112.382473

    CAS  Article  PubMed  Google Scholar 

  74. Schellekens H, De Francesco PN, Kandil D, Theeuwes WF, McCarthy T, van Oeffelen WE, Perello M, Giblin L, Dinan TG, Cryan JF (2015) Ghrelin’s orexigenic effect is modulated via a serotonin 2C receptor interaction. ACS Chem Neurosci. doi:10.1021/cn500318q

    PubMed  Google Scholar 

  75. Schirle NT, Goodman RA, Krishnamurthy M, Beal PA (2010) Selective inhibition of ADAR2-catalyzed editing of the serotonin 2c receptor pre-mRNA by a helix-threading peptide. Org Biomol Chem 8:4898–4904. doi:10.1039/c0ob00309c

    CAS  Article  PubMed  Google Scholar 

  76. Schmauss C, Zimnisky R, Mehta M, Shapiro LP (2010) The roles of phospholipase C activation and alternative ADAR1 and ADAR2 pre-mRNA splicing in modulating serotonin 2C-receptor editing in vivo. RNA 16:1779–1785. doi:10.1261/rna.2188110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Schmidt BJ, Jordan LM (2000) The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord. Brain Res Bull 53:689–710

    CAS  Article  PubMed  Google Scholar 

  78. Serra MJ, Smolter PE, Westhof E (2004) Pronounced instability of tandem IU base pairs in RNA. Nucleic Acids Res 32:1824–1828. doi:10.1093/nar/gkh501

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Shams TA, Muller DJ (2014) Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep 16:473. doi:10.1007/s11920-014-0473-9

    Article  PubMed  Google Scholar 

  80. Shen M, Eyras E, Wu J, Khanna A, Josiah S, Rederstorff M, Zhang MQ, Stamm S (2011) Direct cloning of double-stranded RNAs from RNase protection analysis reveals processing patterns of C/D box snoRNAs and provides evidence for widespread antisense transcript expression. Nucleic Acids Res 39:9720–9730. doi:10.1093/nar/gkr684

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Shen M, Bellaousov S, Hiller M, de La Grange P, Creamer TP, Malina O, Sperling R, Mathews DH, Stoilov P, Stamm S (2013) Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure. Nucleic Acids Res 41:3819–3832. doi:10.1093/nar/gkt063

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Shen JH, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JB, Giller E, Detke MJ, Kane JM (2014) A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res 53:14–22. doi:10.1016/j.jpsychires.2014.02.012

    Article  PubMed  Google Scholar 

  83. Shukla AP, Kumar RB, Aronne LJ (2015) Lorcaserin Hcl for the treatment of obesity. Expert Opin Pharmacother 16:2531–2538. doi:10.1517/14656566.2015.1096345

    CAS  Article  PubMed  Google Scholar 

  84. Singh NN, Androphy EJ, Singh RN (2004) In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA 10:1291–1305

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Soeno Y, Taya Y, Stasyk T, Huber LA, Aoba T, Huttenhofer A (2010) Identification of novel ribonucleo-protein complexes from the brain-specific snoRNA MBII-52. RNA 16:1293–1300

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542–546

    CAS  Article  PubMed  Google Scholar 

  87. Uchida H, Matsumura S, Okada S, Suzuki T, Minami T, Ito S (2017) RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury. FASEB J. doi:10.1096/fj.201600950R

    Google Scholar 

  88. Videtic A, Peternelj TT, Zupanc T, Balazic J, Komel R (2009) Promoter and functional polymorphisms of HTR2C and suicide victims. Genes Brain Behav 8:541–545. doi:10.1111/j.1601-183X.2009.00505.x

    CAS  Article  PubMed  Google Scholar 

  89. Walstab J, Steinhagen F, Bruss M, Gothert M, Bonisch H (2011) Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization. Pharmacol Rep 63:45–53

    CAS  Article  PubMed  Google Scholar 

  90. Walter JS, Sacks J, Othman R, Rankin AZ, Nemchausky B, Chintam R, Wheeler JS (2002) A database of self-reported secondary medical problems among VA spinal cord injury patients: its role in clinical care and management. J Rehabil Res Dev 39:53–61

    PubMed  Google Scholar 

  91. Wang Q, O´Brien PJ, Chen C-X, Cho D-SC, Murray JM, Nishikura K (2000) Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin 2C receptors. J Neurochem 74:1290–1300

    CAS  Article  PubMed  Google Scholar 

  92. Watanabe Y, Yoshimoto K, Tatebe H, Kita M, Nishikura K, Kimura M, Tanaka M (2014) Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors. Int J Neuropsychopharmacol 17:739–751. doi:10.1017/S1461145713001545

    CAS  Article  PubMed  Google Scholar 

  93. Weissmann D, van der Laan S, Underwood MD, Salvetat N, Cavarec L, Vincent L, Molina F, Mann JJ, Arango V, Pujol JF (2016) Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression. Transl Psychiatry 6:e878. doi:10.1038/tp.2016.121

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Yang W, Wang Q, Kanes SJ, Murray JM, Nishikura K (2004) Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. Brain Res Mol Brain Res 124:70–78. doi:10.1016/j.molbrainres.2004.02.010

    CAS  Article  PubMed  Google Scholar 

  95. Zhang J, Shen Y, He G, Li X, Meng J, Guo S, Li H, Gu N, Feng G, He L (2008) Lack of association between three serotonin genes and suicidal behavior in Chinese psychiatric patients. Prog Neuropsychopharmacol Biol Psychiatry 32:467–471. doi:10.1016/j.pnpbp.2007.09.019

    CAS  Article  PubMed  Google Scholar 

  96. Zhang Z, Falaleeva M, Agranat-Tamir L, Pages A, Eyras E, Sperling J, Sperling R, Stamm S (2013) The 5′ untranslated region of the serotonin receptor 2C pre-mRNA generates miRNAs and is expressed in non-neuronal cells. Exp Brain Res 230:387–394. doi:10.1007/s00221-013-3458-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Zhang Z, Shen M, Gresch P, Ghamari-Langroudi M, Rabchevsky AG, Emeson RB, Stamm S (2016) Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake. EMBO molecular medicine 8:878–894. doi:10.15252/emmm.201506030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work was supported by the NIH (R21NS098186) and the Foundation for Prader–Willi Research.

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Correspondence to Stefan Stamm.

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Stamm, S., Gruber, S.B., Rabchevsky, A.G. et al. The activity of the serotonin receptor 2C is regulated by alternative splicing. Hum Genet 136, 1079–1091 (2017). https://doi.org/10.1007/s00439-017-1826-3

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