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Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

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Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is, without doubt, the neurotransmitter for which the number of receptors is the highest. Fifteen genes encoding functional 5-HT receptors have been cloned in mammalian brain. 5-HT3 receptors are ionotropic receptors, whereas all the others are metabotropic G-protein-coupled receptors (GPCRs). 5-HT receptor diversity is further increased by post-genomic modifications, such as alternative splicing (up to 10 splice variants for the 5-HT4 receptor) or by mRNA editing in the case of 5-HT2C receptors. The cellular and behavioral implications of 5-HT2C receptor editing are of great physiological importance. Signaling of 5-HT receptors involves a great variety of pathways, but only some of these have been demonstrated in neurons. The classical view of neurotransmitter receptors localized within the synaptic cleft cannot be applied to 5-HT receptors, which are mostly (but not exclusively) localized at extra-synaptic locations either pre- or post-synaptically. 5-HT receptors are engaged in pre- or post-synaptic complexes composed of many GPCR-interacting proteins. The functions of these proteins are starting to be revealed. These proteins have been implicated in targeting, trafficking to or from the membrane, desensitization, and fine-tuning of signaling.

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References

  • Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F (2005) Strategies for producing faster acting antidepressants. Drug Discov Today 10:578–585

    PubMed  CAS  Google Scholar 

  • Aghajanian GK, Marek GJ(1999a) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161–171

    PubMed  CAS  Google Scholar 

  • Aghajanian GK, Marek GJ(1999b) Serotonin and hallucinogens. Neuropsychopharmacology 21:16S–23S

    PubMed  CAS  Google Scholar 

  • Albert PR, Sajedi N, Lemonde S, Ghahremani MH (1999) Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. J Biol Chem 274:35469–35474

    PubMed  CAS  Google Scholar 

  • Andrade R, Chaput Y(1991) 5-Hydroxytryptamine4 receptors mediate the slow excitatory response to serotonin in the rat hippocampus. J Pharmacol Exp Ther 257:930–937

    PubMed  CAS  Google Scholar 

  • Andrade R, Malenka RC, Nicoll RA (1986) A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 234:1261–1265

    PubMed  CAS  Google Scholar 

  • Ansanay H, Sebben M, Bockaert J, Dumuis A (1992) Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. Mol Pharmacol 42:808–816

    PubMed  CAS  Google Scholar 

  • Ansanay H, Dumuis A, Sebben M, Bockaert J, Fagni L (1995) A cyclic AMP-dependent, long-lasting inhibition of a K+ current in mammalian neurons. Proc Natl Acad Sci USA 92:6635–6639

    PubMed  CAS  Google Scholar 

  • Arvanov VL, Liang X, Russo A, Wang RY (1999) LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex. Eur J Neurosci 11:3064–3072

    PubMed  CAS  Google Scholar 

  • Backstrom JR, Price RD, Reasoner DT, Sanders-Bush E (2000) Deletion of the serotonin 5-HT2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses. J Biol Chem 275:23620–23626

    PubMed  CAS  Google Scholar 

  • Banes AK, Shaw SM, Tawfik A, Patel BP, Ogbi S, Fulton D, Marrero MB (2005) Activation of the JAK/STAT pathway in vascular smooth muscle by serotonin. Am J Physiol Cell Physiol 288:C805–C812

    PubMed  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    PubMed  CAS  Google Scholar 

  • Barthet G, Gaven F, Framery B, Shinjo K, Nakamura T, Claeysen S, Bockaert J, Dumuis A (2005) Uncoupling and endocytosis of 5-hydroxytryptamine 4 receptors. Distinct molecular events with different GRK2 requirements. J Biol Chem 280:27924–27934

    PubMed  CAS  Google Scholar 

  • Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C (2001) Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1. J Biol Chem 276:12974–12982

    PubMed  CAS  Google Scholar 

  • Becamel C, Alonso G, Galeotti N, Demey E, Jouin P, Ullmer C, Dumuis A, Bockaert J, Marin P (2002) Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach. EMBO J 21:2332–2342

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Bender E, Pindon A, Oers I van, Zhang YB, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W (2000) Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant. J Neurochem 74:478–489

    PubMed  CAS  Google Scholar 

  • Berg KA, Harvey JA, Spampinato U, Clarke WP (2005) Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors. Trends Pharmacol Sci 26:625–630

    PubMed  CAS  Google Scholar 

  • Bhatnagar A, Sheffler DJ, Kroeze WK, Compton-Toth B, Roth BL (2004) Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors. J Biol Chem 279:34614–34623

    PubMed  CAS  Google Scholar 

  • Bickmeyer U, Heine M, Manzke T, Richter DW (2002) Differential modulation of I(h) by 5-HT receptors in mouse CA1 hippocampal neurons. Eur J Neurosci 16:209–218

    PubMed  Google Scholar 

  • Bockaert J, Dumuis A (1998) Localization of 5-HT4 receptors in vertebrate brain and their potential roles. Springer, Palo Alto

    Google Scholar 

  • Bockaert J, Sebben M, Dumuis A (1990) Pharmacological characterization of 5-HT4 receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Mol Pharmacol 37:408–411

    PubMed  CAS  Google Scholar 

  • Bockaert J, Fagni L, Dumuis A (1997) 5-HT4 receptors: an update. In: Baumgarten HG, Göthert M (eds) Handbook of experimental pharmacology: serotoninergic neurons and 5-HT receptors in the CNS. Springer, Berlin Heidelberg New York, pp 439–465

    Google Scholar 

  • Bockaert J, Marin P, Dumuis A, Fagni L (2003) The “magic tail” of G protein-coupled receptors: an anchorage for functional protein networks. FEBS Lett 546:65–72

    PubMed  CAS  Google Scholar 

  • Bockaert J, Claeysen S, Compan V, Dumuis A (2004a) 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord 3:39–51

    PubMed  CAS  Google Scholar 

  • Bockaert J, Roussignol G, Becamel C, Gavarini S, Joubert L, Dumuis A, Fagni L, Marin P (2004b) GPCR-interacting proteins (GIPs): nature and functions. Biochem Soc Trans 32:851–855

    PubMed  CAS  Google Scholar 

  • Bockaert J, Claeysen S, Joubert L, Fagni L, Dumuis A (2005) Molecular and cellular determinants of GPCR splice variant constitutive activity. Wiley-VCH, New York

    Google Scholar 

  • Borg J, Andree B, Soderstrom H, Farde L (2003) The serotonin system and spiritual experiences. Am J Psychiatry 160:1965–1969

    PubMed  Google Scholar 

  • Bouhelal R, Smounya L, Bockaert J (1988) 5-HT1B receptors are negatively coupled with adenylate cyclase in rat substantia nigra. Eur J Pharmacol 151:189–196

    PubMed  CAS  Google Scholar 

  • Brailov I, Bancila M, Brisorgueil MJ, Miquel MC, Hamon M, Verge D (2000) Localization of 5-HT(6) receptors at the plasma membrane of neuronal cilia in the rat brain. Brain Res 872:271–275

    PubMed  CAS  Google Scholar 

  • Brattelid T, Kvingedal AM, Krobert KA, Andressen KW, Bach T, Hystad ME, Kaumann AJ, Levy FO (2004) Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i). Naunyn-Schmiedeberg’s Arch Pharmacol 369:616–628

    CAS  Google Scholar 

  • Brezun JM, Daszuta A (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89:999–1002

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Cai X, Flores-Hernandez J, Feng J, Yan Z (2002) Activity-dependent bidirectional regulation of GABA(A) receptor channels by the 5-HT(4) receptor-mediated signalling in rat prefrontal cortical pyramidal neurons. J Physiol (Lond) 540:743–759

    CAS  Google Scholar 

  • Cardenas CG, Del Mar LP, Scroggs RS (1997) Two parallel signaling pathways couple 5HT1A receptors to N- and L-type calcium channels in C-like rat dorsal root ganglion cells. J Neurophysiol 77:3284–3296

    PubMed  CAS  Google Scholar 

  • Carr DB, Cooper DC, Ulrich SL, Spruston N, Surmeier DJ (2002) Serotonin receptor activation inhibits sodium current and dendritic excitability in prefrontal cortex via a protein kinase C-dependent mechanism. J Neurosci 22:6846–6855

    PubMed  CAS  Google Scholar 

  • Chang M, Zhang L, Tam JP, Sanders-Bush E (2000) Dissecting G protein-coupled receptor signaling pathways with membrane-permeable blocking peptides. Endogenous 5-HT(2C) receptors in choroid plexus epithelial cells. J Biol Chem 275:7021–7029

    PubMed  CAS  Google Scholar 

  • Claeysen S, Sebben M, Becamel C, Bockaert J, Dumuis A (1999) Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain. Mol Pharmacol 55:910–920

    PubMed  CAS  Google Scholar 

  • Cogolludo A, Moreno L, Lodi F, Frazziano G, Cobeno L, Tamargo J, Perez-Vizcaino F (2006) Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells. Role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization. Circ Res (in press)

  • Collier HOJ (1958) The occurrence of 5-hydroxytryptamine (5-HT) in nature. Pergamon, New York

    Google Scholar 

  • Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich J, Dumuis A, Brunner D, Bockaert J, Hen R (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci 24:412–419

    PubMed  CAS  Google Scholar 

  • Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187–209

    PubMed  CAS  Google Scholar 

  • Cornea-Hebert V, Watkins KC, Roth BL, Kroeze WK, Gaudreau P, Leclerc N, Descarries L (2002) Similar ultrastructural distribution of the 5-HT(2A) serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat. Neuroscience 113:23–35

    PubMed  CAS  Google Scholar 

  • Day M, Olson PA, Platzer J, Striessnig J, Surmeier DJ (2002) Stimulation of 5-HT(2) receptors in prefrontal pyramidal neurons inhibits Ca(v)1.2 L type Ca(2+) currents via a PLCbeta/IP3/calcineurin signaling cascade. J Neurophysiol 87:2490–2504

    PubMed  CAS  Google Scholar 

  • De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U (2004) Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci 24:3235–3241

    PubMed  Google Scholar 

  • De Vivo M, Maayani S (1986) Characterization of the 5-hydroxytryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther 238:248–253

    PubMed  Google Scholar 

  • Della Rocca GJ, Mukhin YV, Garnovskaya MN, Daaka Y, Clark GJ, Luttrell LM, Lefkowitz RJ, Raymond JR (1999) Serotonin 5-HT1A receptor-mediated Erk activation requires calcium/calmodulin-dependent receptor endocytosis. J Biol Chem 274:4749–4753

    PubMed  CAS  Google Scholar 

  • Descarries L, Beaudet A, Watkins KC (1975) Serotonin nerve terminals in adult rat neocortex. Brain Res 100:563–588

    PubMed  CAS  Google Scholar 

  • Di Matteo V, De Blasi A, Di Giulio C, Esposito E (2001) Role of 5-HT(2C) receptors in the control of central dopamine function. Trends Pharmacol Sci 22:229–232

    PubMed  Google Scholar 

  • Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J (1988) A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 34:880–887

    PubMed  CAS  Google Scholar 

  • Edagawa Y, Saito H, Abe K (1998) 5-HT1A receptor-mediated inhibition of long-term potentiation in rat visual cortex. Eur J Pharmacol 349:221–224

    PubMed  CAS  Google Scholar 

  • Egan CT, Herrick-Davis K, Teitler M (1998) Creation of a constitutively activated state of the 5-hydroxytryptamine2A receptor by site-directed mutagenesis: inverse agonist activity of antipsychotic drugs. J Pharmacol Exp Ther 286:85–90

    PubMed  CAS  Google Scholar 

  • Erspamer V, Asero B (1952) Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169:800–801

    PubMed  CAS  Google Scholar 

  • Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L, Hamon M, Martres MP (2000) Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 12:2299–2310

    PubMed  CAS  Google Scholar 

  • Fagni L, Dumuis A, Sebben M, Bockaert J (1992) The 5-HT4 receptor subtype inhibits K+ current in colliculi neurons via activation of a cyclic AMP-dependent protein kinase. Br J Pharmacol 105:973–979

    PubMed  CAS  Google Scholar 

  • Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR (1999) Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 21:82S–90S

    PubMed  CAS  Google Scholar 

  • Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012

    PubMed  CAS  Google Scholar 

  • Gerard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, Doucet E, Hamon M, Mestikawy S el (1997) Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Res 746:207–219

    PubMed  CAS  Google Scholar 

  • Gingrich JA, Hen R (2001) Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl) 155:1–10

    CAS  Google Scholar 

  • Goaillard JM, Vincent P (2002) Serotonin suppresses the slow afterhyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT(7) receptors. J Physiol (Lond) 541:453–465

    CAS  Google Scholar 

  • Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221

    PubMed  CAS  Google Scholar 

  • Gross C, Hen R (2004) The developmental origins of anxiety. Nat Rev Neurosci 5:545–552

    PubMed  CAS  Google Scholar 

  • Guillet-Deniau I, Burnol AF, Girard J (1997) Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway. J Biol Chem 272:14825–14829

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Harvey JA (2003) Role of the serotonin 5-HT(2A) receptor in learning. Learn Mem 10:355–362

    PubMed  Google Scholar 

  • Hedlund PB, Sutcliffe JG (2004) Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci 25:481–486

    PubMed  CAS  Google Scholar 

  • Heidmann DE, Metcalf MA, Kohen R, Hamblin MW (1997) Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization. J Neurochem 68:1372–1381

    Article  PubMed  CAS  Google Scholar 

  • Higuchi M, Single FN, Kohler M, Sommer B, Sprengel R, Seeburg PH (1993) RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency. Cell 75:1361–1370

    PubMed  CAS  Google Scholar 

  • Hiroi T, Hayashi-Kobayashi N, Nagumo S, Ino M, Okawa Y, Aoba A, Matsui H (2001) Identification and characterization of the human serotonin-4 receptor gene promoter. Biochem Biophys Res Commun 289:337–344

    PubMed  CAS  Google Scholar 

  • Hori Y, Endo K, Takahashi T (1996) Long-lasting synaptic facilitation induced by serotonin in superficial dorsal horn neurones of the rat spinal cord. J Physiol (Lond) 492:867–876

    CAS  Google Scholar 

  • Hoyer D, Martin G (1997) 5-HT receptor classification and nomenclature: towards a harmonization with human genome. Neuropharmacology, 36:419–428

    PubMed  CAS  Google Scholar 

  • Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M, Kaibuchi K (2001) CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4:781–782

    PubMed  CAS  Google Scholar 

  • Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci USA 95:735–740

    PubMed  CAS  Google Scholar 

  • Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X (2006) Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med 12:324–329

    PubMed  CAS  Google Scholar 

  • Johnson MS, Robertson DN, Holland PJ, Lutz EM, Mitchell R (2006) Role of the conserved NPxxY motif of the 5-HT(2A) receptor in determining selective interaction with isoforms of ADP-Ribosylation Factor (ARF). Cell Signal (in press)

  • Joubert L, Hanson B, Barthet G, Sebben M, Claeysen S, Hong W, Marin P, Dumuis A, Bockaert J (2004) New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4a receptor splice variant: roles in receptor targeting. J Cell Sci 117:5367–5379

    PubMed  CAS  Google Scholar 

  • Kajii Y, Muraoka S, Hiraoka S, Fujiyama K, Umino A, Nishikawa T (2003) A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex. Mol Psychiatry 8:434–444

    PubMed  CAS  Google Scholar 

  • Karschin A, Ho BY, Labarca C, Elroy-Stein O, Moss B, Davidson N, Lester HA (1991) Heterologously expressed serotonin 1A receptors couple to muscarinic K+ channels in heart. Proc Natl Acad Sci USA 88:5694–5698

    PubMed  CAS  Google Scholar 

  • Kemp A, Manahan-Vaughan D (2004) Hippocampal long-term depression and long-term potentiation encode different aspects of novelty acquisition. Proc Natl Acad Sci USA 101:8192–8197

    PubMed  CAS  Google Scholar 

  • Kemp A, Manahan-Vaughan D (2005) The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo. Cereb Cortex 15:1037–1043

    PubMed  Google Scholar 

  • Kiel S, Bruss M, Bonisch H, Gothert M (2000) Pharmacological properties of the naturally occurring Phe-124-Cys variant of the human 5-HT1B receptor: changes in ligand binding, G-protein coupling and second messenger formation. Pharmacogenetics 10:655–666

    PubMed  CAS  Google Scholar 

  • Kilbinger H, Wolf D (1992) Effects of 5-HT4 receptor stimulation on basal and electrically evoked release of acetylcholine from guinea-pig myenteric plexus. Naunyn Schmiedebergs Arch Pharmacol 345:270–275

    CAS  Google Scholar 

  • Kilbinger H, Gebauer A, Haas J, Ladinsky H, Rizzi CA (1995) Benzimidazolones and renzapride facilitate acetylcholine release from guinea-pig myenteric plexus via 5-HT4 receptors. Naunyn Schmiedebergs Arch Pharmacol 351:229–236

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kroeze WK, Roth BL (1998) The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis. Biol Psychiatry 44:1128–1142

    PubMed  CAS  Google Scholar 

  • Kvachnina E, Liu G, Dityatev A, Renner U, Dumuis A, Richter DW, Dityateva G, Schachner M, Voyno-Yasenetskaya TA, Ponimaskin EG (2005) 5-HT7 receptor is coupled to Galpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci 25:7821–7830

    PubMed  CAS  Google Scholar 

  • Lanfumey L, Hamon M (2004) 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord 3:1–10

    PubMed  CAS  Google Scholar 

  • Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517

    PubMed  CAS  Google Scholar 

  • Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3:11–26

    PubMed  CAS  Google Scholar 

  • Lezoualc’h F, Robert SJ (2003) The serotonin 5-HT4 receptor and the amyloid precursor protein processing. Exp Gerontol 38:159–166

    PubMed  CAS  Google Scholar 

  • Li P, Zhuo M (1998) Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393:695–698

    PubMed  CAS  Google Scholar 

  • Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M (1999) AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 2:972–977

    PubMed  CAS  Google Scholar 

  • Lin SL, Johnson-Farley NN, Lubinsky DR, Cowen DS (2003) Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac. J Neurochem 87:1076–1085

    PubMed  CAS  Google Scholar 

  • Liu M, Geddis MS, Wen Y, Setlik W, Gershon MD (2005) Expression and function of 5-HT4 receptors in the mouse enteric nervous system. Am J Physiol Gastrointest Liver Physiol 289:G1148–G1163

    PubMed  CAS  Google Scholar 

  • Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (2001) Regional distribution and cellular localization of 5-HT2C receptor mRNA in monkey brain: comparison with [3H]mesulergine binding sites and choline acetyltransferase mRNA. Synapse 42:12–26

    PubMed  CAS  Google Scholar 

  • Lucas G, Debonnel G (2002) 5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphe nucleus 5-HT neuronal activity. Eur J Neurosci 16:817–822

    PubMed  Google Scholar 

  • Lucas G, Compan V, Charnay Y, Neve RL, Nestler EJ, Bockaert J, Barrot M, Debonnel G (2005) Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists. Biol Psychiatry 57:918–925

    PubMed  CAS  Google Scholar 

  • Manivet P, Mouillet-Richard S, Callebert J, Nebigil CG, Maroteaux L, Hosoda S, Kellermann O, Launay JM (2000) PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor. J Biol Chem 275:9324–9331

    PubMed  CAS  Google Scholar 

  • Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW (2003) 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301:226–229

    PubMed  CAS  Google Scholar 

  • Marek GJ, Aghajanian GK (1999) 5-HT2A receptor or alpha1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206

    PubMed  CAS  Google Scholar 

  • Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2000) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87

    PubMed  CAS  Google Scholar 

  • Matsumoto M, Kojima T, Togashi H, Mori K, Ohashi S, Ueno K, Yoshioka M (2002) Differential characteristics of endogenous serotonin-mediated synaptic transmission in the hippocampal CA1 and CA3 fields of anaesthetized rats. Naunyn-Schmiedeberg’s Arch Pharmacol 366:570–577

    CAS  Google Scholar 

  • McGrew L, Chang MS, Sanders-Bush E (2002) Phospholipase D activation by endogenous 5-hydroxytryptamine 2C receptors is mediated by Galpha13 and pertussis toxin-insensitive Gbetagamma subunits. Mol Pharmacol 62:1339–1343

    PubMed  CAS  Google Scholar 

  • McGrew L, Price RD, Hackler E, Chang MS, Sanders-Bush E (2004) RNA editing of the human serotonin 5-HT2C receptor disrupts transactivation of the small G-protein RhoA. Mol Pharmacol 65:252–256

    PubMed  CAS  Google Scholar 

  • Miller KJ (2005) Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv 5:282–291

    PubMed  CAS  Google Scholar 

  • Miner LA, Backstrom JR, Sanders-Bush E, Sesack SR (2003) Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116:107–117

    PubMed  CAS  Google Scholar 

  • Nelson DL (2004) 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord 3:53–58

    PubMed  CAS  Google Scholar 

  • Niesler B, Frank B, Kapeller J, Rappold GA (2003) Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. Gene 310:101–111

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Noda M, Yasuda S, Okada M, Higashida H, Shimada A, Iwata N, Ozaki N, Nishikawa K, Shirasawa S, Uchida M, Aoki S, Wada K (2003) Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways. J Neurochem 84:222–232

    PubMed  CAS  Google Scholar 

  • Norum JH, Hart K, Levy FO (2003) Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J Biol Chem 278:3098–3104

    PubMed  CAS  Google Scholar 

  • Nourry C, Grant SG, Borg JP (2003) PDZ domain proteins: plug and play! Sci STKE 2003:RE7

    Google Scholar 

  • Oleskevich S (1995) G alpha o1 decapeptide modulates the hippocampal 5-HT1A potassium current. J Neurophysiol 74:2189–2193

    PubMed  CAS  Google Scholar 

  • Olsen MA, Nawoschik SP, Schurman BR, Schmitt HL, Burno M, Smith DL, Schechter LE (1999) Identification of a human 5-HT6 receptor variant produced by alternative splicing. Brain Res Mol Brain Res 64:255–263

    PubMed  CAS  Google Scholar 

  • Parker LL, Backstrom JR, Sanders-Bush E, Shieh BH (2003) Agonist-induced phosphorylation of the serotonin 5-HT2C receptor regulates its interaction with multiple PDZ protein 1. J Biol Chem 278:21576–21583

    PubMed  CAS  Google Scholar 

  • Pauwels PJ (1997) 5-HT 1B/D receptor antagonists. Gen Pharmacol 29:293–303

    PubMed  CAS  Google Scholar 

  • Pehek EA, McFarlane HG, Maguschak K, Price B, Pluto CP (2001) M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res 888:51–59

    PubMed  CAS  Google Scholar 

  • Ponimaskin EG, Profirovic J, Vaiskunaite R, Richter DW, Voyno-Yasenetskaya TA (2002) 5-Hydroxytryptamine 4(a) receptor is coupled to the Galpha subunit of heterotrimeric G13 protein. J Biol Chem 277:20812–20819

    PubMed  CAS  Google Scholar 

  • Price RD, Weiner DM, Chang MS, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor alters receptor-mediated activation of G13 protein. J Biol Chem 276:44663–44668

    PubMed  CAS  Google Scholar 

  • Rapport MM, Green AA, Page IH (1948) Serum vasoconstrictor (serotonin). IV. Isolation and characterization. J Biol Chem 176:1243–1251

    PubMed  CAS  Google Scholar 

  • Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN (2001) Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92:179–212

    PubMed  CAS  Google Scholar 

  • Rees S, Daas I den, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M (1994) Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett 355:242–246

    PubMed  CAS  Google Scholar 

  • Riad M, Garcia S, Watkins KC, Jodoin N, Doucet E, Langlois X, el Mestikawy S, Hamon M, Descarries L (2000) Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain. J Comp Neurol 417:181–194

    PubMed  CAS  Google Scholar 

  • Robertson DN, Johnson MS, Moggach LO, Holland PJ, Lutz EM, Mitchell R (2003) Selective interaction of ARF1 with the carboxy-terminal tail domain of the 5-HT2A receptor. Mol Pharmacol 64:1239–1250

    PubMed  CAS  Google Scholar 

  • Roth BL, Ciaranello RD (1991) Chronic mianserin treatment decreases 5-HT2 receptor binding without altering 5-HT2 receptor mRNA levels. Eur J Pharmacol 207:169–172

    PubMed  CAS  Google Scholar 

  • Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs R, Schwartz JC (1993) A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun 193:268–276

    PubMed  CAS  Google Scholar 

  • Sanden N, Thorlin T, Blomstrand F, Persson PA, Hansson E (2000) 5-Hydroxytryptamine2B receptors stimulate Ca2+ increases in cultured astrocytes from three different brain regions. Neurochem Int 36:427–434

    PubMed  CAS  Google Scholar 

  • Sanders-Bush E (1990) Adaptive regulation of central serotonin receptors linked to phosphoinositide hydrolysis. Neuropsychopharmacology 3:411–416

    PubMed  CAS  Google Scholar 

  • Sanders-Bush E, Breeding M (1988) Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus. J Pharmacol Exp Ther 247:169–173

    PubMed  CAS  Google Scholar 

  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

    PubMed  CAS  Google Scholar 

  • Sari Y, Lefevre K, Bancila M, Quignon M, Miquel MC, Langlois X, Hamon M, Verge D (1997) Light and electron microscopic immunocytochemical visualization of 5-HT1B receptors in the rat brain. Brain Res 760:281–286

    PubMed  CAS  Google Scholar 

  • Schlag BD, Lou Z, Fennell M, Dunlop J (2004) Ligand dependency of 5-hydroxytryptamine 2C receptor internalization. J Pharmacol Exp Ther 310:865–870

    PubMed  CAS  Google Scholar 

  • Schoeffter P, Waeber C (1994) 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. Naunyn-Schmiedeberg’s Arch Pharmacol 350:356–360

    CAS  Google Scholar 

  • Sebben M, Ansanay H, Bockaert J, Dumuis A (1994) 5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture. Neuroreport 5:2553–2557

    PubMed  CAS  Google Scholar 

  • Sheffler DJ, Kroeze WK, Garcia BG, Deutch AY, Hufeisen SJ, Leahy P, Bruning JC, Roth BL (2006) p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci USA 103:4717–4722

    PubMed  CAS  Google Scholar 

  • Sodickson DL, Bean BP (1998) Neurotransmitter activation of inwardly rectifying potassium current in dissociated hippocampal CA3 neurons: interactions among multiple receptors. J Neurosci 18:8153–8162

    PubMed  CAS  Google Scholar 

  • Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci 2:1144–1154

    PubMed  Google Scholar 

  • Starke K, Gothert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 69:864–989

    PubMed  CAS  Google Scholar 

  • Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, Yacoubi ME, Vaugeois JM, Nomikos GG, Greengard P (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80

    PubMed  CAS  Google Scholar 

  • Thomas DR, Hagan JJ (2004) 5-HT7 receptors. Curr Drug Targets CNS Neurol Disord 3:81–90

    PubMed  CAS  Google Scholar 

  • Torres GE, Arfken CL, Andrade R (1996) 5-Hydroxytryptamine4 receptors reduce after-hyperpolarization in hippocampus by inhibiting calcium-induced calcium release. Mol Pharmacol 50:1316–1322

    PubMed  CAS  Google Scholar 

  • Turner JH, Raymond JR (2005) Interaction of calmodulin with the serotonin 5-hydroxytryptamine2A receptor. A putative regulator of G protein coupling and receptor phosphorylation by protein kinase C. J Biol Chem 280:30741–30750

    PubMed  CAS  Google Scholar 

  • Turner JH, Gelasco AK, Raymond JR (2004) Calmodulin interacts with the third intracellular loop of the serotonin 5-hydroxytryptamine1A receptor at two distinct sites: putative role in receptor phosphorylation by protein kinase C. J Biol Chem 279:17027–17037

    PubMed  CAS  Google Scholar 

  • Ullmer C, Schmuck K, Figge A, Lubbert H (1998) Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Lett 424:63–68

    PubMed  CAS  Google Scholar 

  • Van Hooft JA, Yakel JL (2003) 5-HT3 receptors in the CNS: 3B or not 3B? Trends Pharmacol Sci 24:157–160

    PubMed  Google Scholar 

  • Van Oekelen D, Luyten WH, Leysen JE (2003) 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci 72:2429–2449

    PubMed  Google Scholar 

  • Villalobos C, Beique JC, Gingrich JA, Andrade R (2005) Serotonergic regulation of calcium-activated potassium currents in rodent prefrontal cortex. Eur J Neurosci 22:1120–1126

    PubMed  Google Scholar 

  • Wainscott DB, Cohen ML, Schenck KW, Audia JE, Nissen JS, Baez M, Kursar JD, Lucaites VL, Nelson DL (1993) Pharmacological characteristics of the newly cloned rat 5-hydroxytryptamine2F receptor. Mol Pharmacol 43:419–426

    PubMed  CAS  Google Scholar 

  • Weiss S, Pin J-P, Sebben M, Kemp D, Sladeczek F, Gabrion J, Bockaert J (1986) Synaptogenesis of cultured striatal neurones in serum-free medium: a morphological and biochemical study. Proc Natl Acad Sci USA 83:2238–2242

    PubMed  CAS  Google Scholar 

  • Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22:2843–2854

    PubMed  CAS  Google Scholar 

  • Willins DL, Berry SA, Alsayegh L, Backstrom JR, Sanders-Bush E, Friedman L, Roth BL (1999) Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo. Neuroscience 91:599–606

    PubMed  CAS  Google Scholar 

  • Woolley ML, Marsden CA, Fone KC (2004) 5-HT6 receptors. Curr Drug Targets CNS Neurol Disord 3:59–79

    PubMed  CAS  Google Scholar 

  • Xia Z, Gray JA, Compton-Toth BA, Roth BL (2003a) A direct interaction of PSD95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem 278:21901–21908

    PubMed  CAS  Google Scholar 

  • Xia Z, Hufeisen SJ, Gray JA, Roth BL (2003b) The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro. Neuroscience 122:907–920

    PubMed  CAS  Google Scholar 

  • Xie E, Zhu L, Zhao L, Chang LS (1996) The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant. Genomics 35:551–561

    PubMed  CAS  Google Scholar 

  • Yan W, Wilson CC, Haring JH (1997) 5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. Brain Res Dev Brain Res 98:185–190

    PubMed  CAS  Google Scholar 

  • Yuen EY, Jiang Q, Chen P, Gu Z, Feng J, Yan Z (2005) Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci 25:5488–5501

    PubMed  CAS  Google Scholar 

  • Zhou FM, Hablitz JJ (1999) Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex. J Neurophysiol 82:2989–2999

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. CNRS, UMR5203, Montpellier, F-34094, France

    Joël Bockaert, Sylvie Claeysen, Carine Bécamel, Aline Dumuis & Philippe Marin

  2. INSERM, U661, Montpellier, F-34094, France

    Joël Bockaert, Sylvie Claeysen, Carine Bécamel, Aline Dumuis & Philippe Marin

  3. Univ Montpellier I, Montpellier, F-34094, France

    Joël Bockaert, Sylvie Claeysen, Carine Bécamel, Aline Dumuis & Philippe Marin

  4. Univ Montpellier II, Montpellier, F-34094, France

    Joël Bockaert, Sylvie Claeysen, Carine Bécamel, Aline Dumuis & Philippe Marin

  5. Institut de Génomique Fonctionnelle, Département de Neurobiologie, 141 Rue de la Cardonille, Montpellier, Cedex 5, F-34094, France

    Joël Bockaert, Sylvie Claeysen, Carine Bécamel, Aline Dumuis & Philippe Marin

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  1. Joël Bockaert
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Bockaert, J., Claeysen, S., Bécamel, C. et al. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 326, 553–572 (2006). https://doi.org/10.1007/s00441-006-0286-1

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