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5-HT4 Receptors in the Brain and Periphery pp 49–61Cite as

Molecular Biology of 5-HT4 Receptors

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Part of the book series: Biotechnology Intelligence Unit ((BIOIU))

Abstract

Serotonin is a neurotransmitter involved in a plethora of physi-ological functions exerted through its interaction with numerous receptor subtypes throughout the body. Using pharmacological approaches, four distinct receptor classes were defined: 5-HT1, 5-HT2, 5-HT3 and 5-HT4.27 However, molecular biological studies have provided both primary amino acid sequence and signal transduction data for a much larger than anticipated array of serotonin receptor subtypes, comprising seven major families: five 5-HT1, three 5-HT2, one 5-HT3, one 5-HT4, two 5-HT5, one 5-HT6 and one 5-HT7 receptor. The majority of these receptors are members of the G-proteincoupled receptor superfamily, which are characterized by a seven transmembrane (TM) spanning arrangement of a helices, proposed to form a barrel-like structure in the membrane.8 The cloned 5-HT1, receptors are: 5-HT1A,19,31 5-HT1B,1,44,28,37,52,54 5-HT1D,11,25,54 5-HT1E 33,39,55 and 5-HT1F.2,6,35 The major signal transduction pathway for each subtype is the inhibition of adenylate cyclase activity. The 5-HT2 receptors include: 5-HT2A,45 5-HT2B 20,32 and 5-HT2C.29 The primary signal transduction pathway of each of these receptors is phosphoinositide hydrolysis. The 5-HT3 receptor is not a G-protein-coupled receptor, it is a ligand-gated ion channel.36 The 5-HT5A and 5-HT5B receptors are similar in pharmacological profile, but not primary structure, to some 5-HT1, receptors.18,38 The signal transduction pathways for these subtypes remain elusive, and the 5-HT5B subtype appears to be a pseudogene in the human.23 Of the seven families, three signal their activation via the stimulation of cAMP production. The 5-HT4 receptor is a member of this cyclase stimulatory serotonin receptor set.12,22 Both 5-HT6 40 and 5-HT7, receptors7,34,44,47,48 are also coupled to stimulation of adenylate cyclase. Although one of the early subtypes to be characterized pharmacologically, the 5-HT4 receptor was the last to be cloned.

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References

  1. Adham N, Romanienko P, Hartig P et al. The rat 5-hydroxytryptamine,B receptor is the species homologue of the human 5hydroxytryptamine,Dp receptor. Mol Pharmacol 1992; 41: 1–7.

    PubMed  CAS  Google Scholar 

  2. Adham N, Kao HT, Schechter LE et al. Cloning of another human serotonin receptor (5-HT,F): A fifth 5-HT, receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 1993; 90: 408–412.

    Article  PubMed  CAS  Google Scholar 

  3. Adham N, Gerald C, Vaysse PJJ et al. Differential sensitivity of the short and long rat 5-HT4 receptor subtypes to desensitization. Soc Neurosci Abstr 1995; 21: 773.

    Google Scholar 

  4. Adham N, Gerald C, Schechter L et al. [3H]5-Hydroxytryptamine labels the agonist high affinity state of the cloned rat 5-HT4 receptor. Eur J Pharmacol 1996; 304: 231–235.

    Article  PubMed  CAS  Google Scholar 

  5. Albert PR, Zhon QY, VonTol HHM et al. Cloning, functional expression and mRNA tissue distribution of the rat 5-hydroxytryptamine,A receptor gene. J Biol Chem 1990; 265: 5825–5832.

    PubMed  CAS  Google Scholar 

  6. Amlaiky N, Ramboz S, Boschert U et al. Isolation of a mouse “5HT1E-like” serotonin receptor expressed predominantly in hippo-campus. J Biol Chem 1992; 267: 19761–19764.

    PubMed  CAS  Google Scholar 

  7. Bard JA, Zgombick J, Adham N et al. Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem 1993; 268: 23422–23426.

    PubMed  CAS  Google Scholar 

  8. Baldwin JM. The probable arrangement of the helices in G protein-coupled receptors. EMBO J 1993; 12: 1693–1703.

    PubMed  CAS  Google Scholar 

  9. Bockaert J, Fozard JR, Dumuis A et al. The 5-HT4 receptor: A place in the sun. Trends Pharmacol Sci 1992; 13: 141–145.

    Article  PubMed  CAS  Google Scholar 

  10. Bonhaus DW, Berger J, Adham N et al. [3H]RS 57639, a high affinity, selective 5-HT4 receptor partial agonist, specifically labels guinea-pig striatal and rat cloned (5-HT4s and 5-HT4L) receptors. Neuropharmacol 1997; 36: 671–679.

    Article  CAS  Google Scholar 

  11. Branchek TA, Zgombick JM, Macchi MJ et al. Cloning and expression of a human 5-HT,D receptor. In: Saxena P, Fozard JR, eds. Serotonin: Molecular Biology, Receptors, and Functional Effects. Basel: Birkhauser 1991: 21–32.

    Chapter  Google Scholar 

  12. Branchek TA. 5-HT4, 5-HT6i 5-HT7; molecular pharmacology of adenylate cyclase stimulating receptors. Seminars in The Neurosciences 1995; 7:375–382.

    Google Scholar 

  13. Claeysen S, Sebben M, Journot L et al. Cloning, expression and pharmacology of the mouse 5-HT4L receptor. FEBS Lett 1996; 398: 19–25.

    Article  PubMed  CAS  Google Scholar 

  14. Demchyshyn L, Sunahara RK, Miller K et al. A human serotonin 1D receptor variant (5-HT,Dp) encoded by an intronless gene on chromosome 6. Proc Natl Acad Sci USA 1992; 89: 5522–5526.

    Article  PubMed  CAS  Google Scholar 

  15. Dumuis A, Bouhelal R, Sebben M et al. A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 1988; 34: 880–887.

    PubMed  CAS  Google Scholar 

  16. Dumuis A, Sebben M, Bockaert J. BRL 24924: A potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. Eur J Pharmacol 1989; 162: 381–384.

    Article  PubMed  CAS  Google Scholar 

  17. Eglen RM, Wong EHF, Dumuis A et al. Central 5-HT4 receptors. Trends Pharmacol Sci 1995; 16: 391–398.

    Article  PubMed  CAS  Google Scholar 

  18. Erlander MG, Lovenberg TW, Baron BM et al. Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain. Proc Natl Acad Sci USA 1993; 90: 3452–3456.

    Article  PubMed  CAS  Google Scholar 

  19. Fargin A, Raymond JR, Lohse MJ et al. The genomic clone G-21 which resembles a p-adrenergic receptor sequence encodes the 5-HT1A receptor. Nature 1988; 335: 358–360.

    Article  PubMed  CAS  Google Scholar 

  20. Foguet M, Hoyer D, Pardo LA et al. Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 1992; 11: 3481–3487.

    PubMed  CAS  Google Scholar 

  21. Gerald C, Adham N, Vaysse PJJ et al. The 5-HT4 receptor: Molecular cloning and pharmacological characterization of the human 5-HT4L receptor. Soc Neurosci Abstr 1994; 20: 1266.

    Google Scholar 

  22. Gerald C, Adham, N, Kao HT et al. The 5-HT4 receptor: Molecular cloning and pharmacological characterization of two splice variants. EMBO J 1995; 14(12):2806–2815.

    Google Scholar 

  23. Grailhe R, Ramboz U, Hen R. The 5-HT5 receptors: Characterization of the human 5-HT5A receptor; absence of the human 5-HT5B receptor; knockout of the mouse 5-HT5A receptor. Soc Neurosci Abstr 1995; 21: 1856.

    Google Scholar 

  24. Grossman CJ, Kilpatrick GJ, Bunce KT. Development of a radioligand binding assay for s-HT4 receptors in guinea pig and rat brain. Br J Pharmacol 1993; 109: 618–624.

    Article  PubMed  CAS  Google Scholar 

  25. Hamblin MW, Metcalf MA. Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor. Mol Pharmacol 1991; 40: 143–148.

    PubMed  CAS  Google Scholar 

  26. Hamblin MW, McGuffin RW, Metcalf MA et al. Distinct 5-HT1B and 5-HT1D serotonin receptors in rat: structural and pharmacological comparison of the two cloned receptors. Mol and Cell Neurosci 1992; 3: 578–587.

    Article  CAS  Google Scholar 

  27. Humphrey PPA, Hartig P, Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 1993; 14: 233–236.

    Article  PubMed  CAS  Google Scholar 

  28. Jin H, Oksenberg D, Ashkenazi A et al. Characterization of the human 5-hydroxytryptamine1B receptor. J Biol Chem 1992; 267: 5735–5738.

    PubMed  CAS  Google Scholar 

  29. Julius D, MacDermott AB, Axel R et al. Molecular characterization of a functional cDNA encoding the serotoninlc receptor. Science 1988; 241: 558–564.

    Article  PubMed  CAS  Google Scholar 

  30. Julius D, Huang KN, Livelli TJ et al. The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors. Proc Natl Acad Sci 1990; 87: 928–932.

    Article  PubMed  CAS  Google Scholar 

  31. Kobilka BK, Frielle T, Collins S et al. An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature 1987; 329: 75–79.

    Article  PubMed  CAS  Google Scholar 

  32. Kursar JD, Nelson DL, Wainscott DB et al. Molecular cloning, functional expression, and pharmacological characterization of a novel serotonin receptor (5-hydroxytryptamine2F) from rat stomach fun-dus. Mol Pharmacol 1992; 42: 549–557.

    PubMed  CAS  Google Scholar 

  33. Levy FO, Gudermann T, Birnbaumer M et al. Molecular cloning of a human gene (S31) encoding a novel serotonin receptor mediating inhibition of adenylyl cyclase. FEBS Lett 1992; 296: 201–206.

    Article  PubMed  CAS  Google Scholar 

  34. Lovenberg TW, Baron BM, De Lecea L et al. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron 1993; 11:449–458.

    Article  PubMed  CAS  Google Scholar 

  35. Lovenberg TW, Erlander MG, Baron BM et al. Molecular cloning and functional expression of 5-HT1E-like rat and human 5-hydroxytryptamine receptor genes. Proc Natl Acad Sci USA 1993; 90: 2184–2188.

    Article  PubMed  CAS  Google Scholar 

  36. Maricq AV, Peterson AV, Brake AJ et al. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 1991; 254: 432–436.

    Article  PubMed  CAS  Google Scholar 

  37. Maroteaux L, Saudou F, Amlaiky N et al. Mouse 5HT1B serotonin receptor: Cloning, functional expression and localization in motor control centers. Proc Natl Acad Sci USA 1992; 89: 3020–3024.

    Article  PubMed  CAS  Google Scholar 

  38. Matthes H, Boschert U, Amlaiky N et al. Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: Cloning, functional expression and chromosomal localization. Mol Pharmacol 1993; 43: 313–319.

    PubMed  CAS  Google Scholar 

  39. McAllister G, Charlesworth A, Snodin C et al. Molecular cloning of a serotonin receptor from human brain (5HT1E): A fifth 5HT,- like subtype. Proc Natl Acad Sci USA 1992; 89: 5517–5521.

    Article  PubMed  CAS  Google Scholar 

  40. Monsma FJ, Shen Y, Ward RP et al. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol 1993; 43: 320–327.

    PubMed  CAS  Google Scholar 

  41. Namba T, Sugimoto Y, Negishi M et al. Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity. Nature 1993; 365: 166–170.

    CAS  Google Scholar 

  42. Ng GYK, George SR, Zastawny RL et al. Human serotonin1B receptor expression in Sf9 cells: phosphorylation, palmitoylation and adenylyl cyclase inhibition. Biochemistry 1993; 32: 11727–11733.

    Article  PubMed  CAS  Google Scholar 

  43. O’Dowd BF, Hnatowich M, Caron MG et al. Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J Biol Chem 1989; 264: 7564–7569.

    PubMed  Google Scholar 

  44. Plassat JL, Amlaiky N, Hen R. Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol Pharmacol 1993; 44: 229–236.

    PubMed  CAS  Google Scholar 

  45. Pritchett DB, Bach AWJ, Wozny M et al. Structure and functional expression of cloned rat serotonin 5HT-2 receptor. EMBO J 1988; 7: 4135–4140.

    PubMed  CAS  Google Scholar 

  46. Reisine T, Kong H, Raynor K et al. Splice variant of the somatostatin receptor 2 subtype, somatostatin receptor 2B, couples to adenylyl cyclase. Mol Pharmacol 1993; 44: 1016–1020.

    PubMed  CAS  Google Scholar 

  47. Ruat M, Traiffort E, Leurs R et al. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci USA 1993; 90: 8547–8551.

    Google Scholar 

  48. Shen Y, Monsma FJ, Metcalf MA et al. Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. J Biol Chem 1993; 268: 18200–18204.

    PubMed  CAS  Google Scholar 

  49. Ullmer C, Schmuck K, Kalkman HO et al. Expression of serotonin receptor mRNAs in blood vessels. FEBS Lett 1995; 370: 215–221.

    Article  PubMed  CAS  Google Scholar 

  50. Vanetti M, Kouba M, Wang X et al. Cloning and expression of a novel mouse somatostatin receptor. FEBS Lett 1992; 311: 290–294.

    Article  PubMed  CAS  Google Scholar 

  51. Vanetti M, Vogt G, Hollt V. The two isoforms of the mouse somatostatin receptor (mSSTR2A and mSSTR2B) differ in coupling efficiency to adenylate cyclase and in agonist-induced receptor desensitization. FEBS Lett 1993; 331: 260–266.

    Article  PubMed  CAS  Google Scholar 

  52. Voigt MM, Laurie DJ, Seeburg PH et al. Molecular cloning and characterization of a rat brain cDNA encoding a 5-hydroxytryptaminelB receptor. EMBO J 1991; 10: 4017–4023.

    PubMed  CAS  Google Scholar 

  53. Waeber C, Sebben M, Grossman C et al. [3H]-GR113808 labels 5-HT4 receptors in the human and guinea-pig brain. Neuroreport 1993; 4: 1239–1242.

    Google Scholar 

  54. Weinshank RL, Zgombick JM, Macchi M et al. Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D« and 5-HT1Dp. Proc Natl Acad Sci USA 1992; 89: 3630–3634.

    Article  PubMed  CAS  Google Scholar 

  55. Zgombick JM, Schechter LE, Macchi M et al. Human gene S31 encodes the pharmacologically defined serotonin 5-hydroxytryptaminelE receptor. Mol Pharmacol 1992; 42: 180–185.

    PubMed  CAS  Google Scholar 

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Authors
  1. Theresa A. Branchek
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  2. Nika Adham
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  3. Christophe Gerald
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Editors and Affiliations

  1. Roche Bioscience, Palo Alto, California, USA

    Richard M. Eglen Ph.D.

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© 1998 Springer-Verlag Berlin Heidelberg

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Branchek, T.A., Adham, N., Gerald, C. (1998). Molecular Biology of 5-HT4 Receptors. In: Eglen, R.M. (eds) 5-HT4 Receptors in the Brain and Periphery. Biotechnology Intelligence Unit. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-05553-3_2

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  • DOI: https://doi.org/10.1007/978-3-662-05553-3_2

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-05555-7

  • Online ISBN: 978-3-662-05553-3

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