Molecular Neurobiology

, Volume 29, Issue 1, pp 31–39

Multiple signal transduction pathways mediated by 5-HT receptors

  • Mami Noda
  • Haruhiro Higashida
  • Shunsuke Aoki
  • Keiji Wada
Article

Abstract

Among human serotonin (5-HT) receptor subtypes, each G protein-coupled receptor subtype is reported to have one G protein-signaling cascade. However, the signaling may not be as simple as previously thought to be. 5-HT5A receptors are probably the least well understood among the 5-HT receptors, but the authors found that 5-HT5A receptors couple to multiple signaling cascades. When the 5-HT5A receptors were expressed in undifferentiated C6 glioma cells, they modulated the level of second messengers. For example, activation of 5-HT5A receptors inhibited the adenylyl cyclase activity and subsequently reduced the cAMP level, as previously reported. In addition to this known signaling via Gi/Go, 5-HT5A receptors are coupled to the inhibition of ADP-ribosyl cyclase and cyclic ADP ribose formation. On the other hand, activation of 5-HT5A receptors transiently opened the K+ channels, presumably due to the increase in intracellular Ca2+ after formation of inositol (1,4,5) trisphosphate. The K+ currents were inhibited by both heparin and pretreatment with pertussis toxin, suggesting the cross-talk between Gi/Go protein and phopholipase C cascade. Thus, the authors results indicate that 5-HT5A receptors couple to multiple second messenger systems and may contribute to the complicated physiological and pathophysiological states. Although this multiple signaling has been reported only for 5-HT5A/5-HT1 receptors so far, it is possible that other 5-HT receptor subtypes bear similar complexity. As a result, in addition to the wide variety of expression patterns of each 5-HT receptor subtype, it is possible that multiple signal transduction systems may add complexity to the serotonergic system in brain function. The investigation of these serotonergic signaling and its impairment at cellular level may help to understand the symptoms of brain diseases.

Index Entries

5-HT5A receptors Gi/Go adenylyl cyclase cyclic AMP ADP ribosyl cyclase cyclic ADP ribose IP3 K+ channels 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Barnes N. M. and Sharp T. (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083–1152.PubMedCrossRefGoogle Scholar
  2. 2.
    Albert P. R. and Tiberi M. (2001) Receptor signaling and structure: insights from serotonin-1 receptors. Trends Endocrinol. Metab. 12, 453–460.PubMedCrossRefGoogle Scholar
  3. 3.
    Noda M., Yasuda S., Okada M., et al. (2003) Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways. J. Neurochem. 84, 222–232.PubMedCrossRefGoogle Scholar
  4. 4.
    Plassat J.-L., Boschert U., Amlaiky N., and Hen R. (1992) The mouse 5-HT5 receptor reveals a remarkable heterogeneity within the 5-HT1D receptor family. EMBO J. 11, 4779–4786.PubMedGoogle Scholar
  5. 5.
    Matthes H., Boschert U., Amlaiky N., et al. (1993) Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol. Pharmacol. 43, 313–319.PubMedGoogle Scholar
  6. 6.
    Erlander M. G., Lovenberg T. W., Baron B. M., et al. (1993) Two members of a distinct subfamily of 6-hydroxytryptamine receptors differentially expressed in rat brain. Prc. Natl. Acad. Sci. USA 90, 3452–3456.CrossRefGoogle Scholar
  7. 7.
    Wisden W., Parker E. M., Mahle C. D., et al. (1993) Cloning and characterization of the rat 5-HT5B receptor. Evidence that the 5-HT5B receptor couples to a G protein in mammalian cell membranes. FEBS Lett. 333, 25–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Rees S., den Daas I., Foord S., Goodson S., Bull D., Kilpatrick G., and Lee M. (1994) Cloning and characterization of the human 5-HT5A serotonin receptor. FEBS Lett. 355, 242–246.PubMedCrossRefGoogle Scholar
  9. 9.
    Shimron-Abarbanell D., Erdmann J., Vogt I. R., et al. (1997) Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5′ untranslated region. Biochem Biophys. Res. Commun. 233, 6–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Grailhe R., Grabtree G. W., and Hen R. (2001) Human 5-HT5A receptor; the 5-HT5A receptor is functional but the 5-HT5B receptor was lost during mammalian evolution. Eur. J. Pharmacol. 418, 157–167.PubMedCrossRefGoogle Scholar
  11. 11.
    Weiß H. M., Haase W., Michel H., and Reiländer H. (1995) Expression of functional mouse 5-HT5A serotonin receptor in the methylotrophic yeast Pichia pastoris: pharmacological characterization and localization. FEBS Lett. 377, 451–456.PubMedCrossRefGoogle Scholar
  12. 12.
    Humphrey P. P. A. (1997) The characterization and classification of neurotransmitter receptors. Ann. NY Acad. Sci. 812, 1–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Pasqualetti M., Ori M., Nardi I., Castagna M., Cassano G. B., and Marazzoto D. (1998) Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol. Brain Res. 56, 1–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Carson M. J., Thomas E. A., Danielson P. E., and Sutcliffe J. G. (1996) The 5-HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: A mechanism for neuronal suppression of reactive astrocytes. GLIA 17, 317–326.PubMedCrossRefGoogle Scholar
  15. 15.
    Branchet T. A. and Zgombick J. M. (1997) Molecular biology and potential functional role of 5-HT5, 5-HT6, and 5-HT7 receptors, in Handbook of Experimental Pharmacology. Serotonergic Neurons and 5-HT Receptors in the CNS, Baumgarten H. G. and Güther M., eds., Springer-Verlag, Berlin pp. 475–497.Google Scholar
  16. 16.
    Wang Z. Y., Keith I. M., Beckman M. J., Brownfield M. S., Vidruk E. H., and Bisfard G. E. (2000) 5-HT5A receptors in the carotid body chemoreception pathway of rat. Neurosci Lett. 278, 9–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Grailhe R., Waeber C., Dulawa S. C., Hornung J. P., Zhuang X., Brunner D., Geyer M. A., and Hen R. (1999) Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor. Neuron 22, 581–591.PubMedCrossRefGoogle Scholar
  18. 18.
    Iwata N., Ozaki N., Inada T., and Goldman D. (2001) Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schiphrenia. Mol. Psychiatry 6, 217–219.PubMedCrossRefGoogle Scholar
  19. 19.
    Birkett J. T., Arranz M. J., Munro J., Osbourn S., Kerwin R. W., and Collier D. A. (2000) Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. NeuroReport 11, 2017–2020.PubMedCrossRefGoogle Scholar
  20. 20.
    Arias B., Collier D. A., Gasto C., Pintor L., Gutierres B., Valles V., and Fananas L. (2001) Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci. Lett. 303, 111–114.PubMedCrossRefGoogle Scholar
  21. 21.
    Kinsey A. M., Wainwright A., Heavens R., Sirinathsinghji D. J., and Oliver K. R. (2001) Distribution of 5-ht(5A), 5-ht(5B), 5-ht(6) and 5-HT(7) receptor mRNAs in the rat brain. Brain Res. Mol. Brain Res. 88, 194–198.PubMedCrossRefGoogle Scholar
  22. 22.
    Oliver K. R., Kinsey A. M., Wainwright A., and Sirinathsinghji D. J. (2000) Localization of 5-ht(5A) receptor-like immunoreactivity in the rat brain. Brain Res. 867, 131–142.PubMedCrossRefGoogle Scholar
  23. 23.
    Duncan M. J., Jennes L., Jefferson J. B., and Brownfield M. S. (2000) Localization of serotonin(5A) receptors in discrete regions of the circadian timing system in the Syrian hamster. Brain Res. 869, 178–185.PubMedCrossRefGoogle Scholar
  24. 24.
    Marazziti D., Ori M., Nardini M., Rossi A., Nardi I., and Cassano G. B. (2001) mRNA expression of serotonin receptors of type 2C and 5A in human resting lymphocytes. Neuropsychobiology 43, 123–126.PubMedCrossRefGoogle Scholar
  25. 25.
    Hurley P. T., McMahon R. A., Fanning P., O’Boyle K. M., Rogers M., and Martin F. (1998) Functional coupling of a recombinant human 5-HT5a receptor to G-proteins in HEK-293 cells. Br. J. Pharmacol. 124, 1238–1244.PubMedCrossRefGoogle Scholar
  26. 26.
    Francken B. J. B., Jurzak M., Vanhauwe J. F. M., Luyten W. H. M. L., and Leysen J. E. (1998) The human 5-HT5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK293 cells. Eur. J. Pharmacol. 361, 299–309.PubMedCrossRefGoogle Scholar
  27. 27.
    Thomas E. A., Matli J. R., Hu J. L., Carson M. J., and Sutcliffe J. G. (2000) Purtussis toxin treatment prevents 5-HT5A receptor-mediated inhibition of cyclic AMP Accumulation in rat C6 glioma cells. J. Neurosci. Res. 61, 75–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Galione A., Lee H. C., and Busa W. B. (1991) Ca(2+)-induced Ca2+ release in sea urchin egg homogenates: modulation by cyclic ADP-ribose. Science 253, 1143–1146.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee H. C., Aarhus R., and Walseth T. F. (1993) Calcium mobilization by dual receptors during fertilization of sea urchin eggs. Science 261, 352–355.PubMedCrossRefGoogle Scholar
  30. 30.
    Meszaros L. G., Bak J., and Chu A. (1993) Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca2+ channel. Nature 364, 76–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Higashida H., Hashii M., Yokoyama S., Hoshi N., Chen X. L., Egorova A., Noda M., and Zhang J. S. (2001) Cyclic ADP-ribose as a second messenger revisited from a new aspect of signal transduction from receptors to ADP-ribosyl cyclase. Pharmacol. Ther. 90, 283–296.PubMedCrossRefGoogle Scholar
  32. 32.
    Morita K., Kitayama S., and Dohi T. (1997) Stimulation of cyclic ADP-ribose synthesis by acetylcholine and its role in catecholamine release in bovine adrenal chromaffin cells. J. Biol. Chem. 272, 21,002–21,009.Google Scholar
  33. 33.
    Mothet J. P., Fossier P., Meunier F. M., Stinnakre J., Tauc L., and Baux G. (1998) Cyclic ADP-ribose and calcium-induced calcium release regulate neurotransmitter release at a cholinergic synapse of Aplysia. J. Physiol. 507, 405–414.PubMedCrossRefGoogle Scholar
  34. 34.
    Brailoiu E. and Miyamoto M. D. (2000) Inositol trisphosphate and cyclic adenosine diphosphate-ribose increase quantal transmitter release at frog motor nerve terminals: possible involvement of smooth endoplasmic reticulum. Neuroscience 95, 927–931.PubMedCrossRefGoogle Scholar
  35. 35.
    Kato I., Takasawa S., Akabane A., et al. (1995) Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic beta cells. Enhancedinsulin secretion in CD38-expressing transgenic mice. J. Biol. Chem. 270, 30,045–30,050.Google Scholar
  36. 36.
    Reyes-Harde M., Empson R., Potter B. V., Galione A., and Stanton P. K. (1999a) Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus. Proc. Natl. Acad. Sci USA 96, 4061–4066.PubMedCrossRefGoogle Scholar
  37. 37.
    Reyes-Harde M., Potter B. V., Galion A., and Stanton P. K. (1999b) Induction of hippocampal LTD requires nitric-oxide-stimulated PKG activity and Ca2+ release from cyclic ADP-ribose-sensitive stores. J. Neurophysiol. 82, 1569–1576.PubMedGoogle Scholar
  38. 38.
    White T. A., Walseth T. F., and Kannan M. S. (2002) Nitric oxide inhibits ADP-ribosyl cyclase through a cGMP-independent pathway in airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 283, L1065–1071.PubMedGoogle Scholar
  39. 39.
    Zocchi E., Carpaneto A., Cerrano C., et al. (2001) The temperature-signaling cascade in sponges involves a heat-gated cation channel, abscisic acid, and cyclic ADP-ribose. Proc. Natl. Acad. Sci USA 98, 14,859–14,864.CrossRefGoogle Scholar
  40. 40.
    Ehrlich B. E., Kaftan E., Bezprozvannaya S., and Bezprozvanny I. (1994) The pharmacology of intracellular Ca(2+)-release channels. Trends Pharmacol. Sci. 15, 145–149.PubMedCrossRefGoogle Scholar
  41. 41.
    Noda M., Katayama M., Brown D. A., et al. (1993) Coupling of m2 and m4 muscarinic acetylcholine receptor subtypes to Ca2+-dependent K+ channels in transformed NL308 neuroblastoma × fibroblast hybrid cells. Proc. R. Soc. Lond. B. 251, 215–224.CrossRefGoogle Scholar
  42. 42.
    Ishizaka N., Noda M., Kimura Y., et al. (1995) Inositol 1,4,5-trisphosphate formation and ryanodine-sensitive oscillations of cytosolic free Ca2+ concentrations in neuroblastoma × fibroblast hybrid NL308 cells expressing m2 and m4 muscarinic acetylcholine receptor subtypes. Pflügers Arch. Eur. J. Physiol. 429, 426–433.CrossRefGoogle Scholar
  43. 43.
    Mann J. J. (2003) Neurobiology of suicidal behaviour. Nat. Rev. Neurosci. 4, 819–828.PubMedCrossRefGoogle Scholar
  44. 44.
    Muller C. P., Carey R. J., Huston J. P. (2003) Serotonin as an important mediator of cocaine’s behavioral effects. Drugs Today (Barc) 39, 497–511.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Mami Noda
    • 1
  • Haruhiro Higashida
    • 2
  • Shunsuke Aoki
    • 3
  • Keiji Wada
    • 3
  1. 1.Laboratory of PathophysiologyKyushu University Graduate School of Pharmaceutical SciencesFukuoka
  2. 2.Department of Biophysical GeneticsKanazawa University Graduate School of MedicineKanazawa
  3. 3.Department of Degenerative Neurological DiseasesNational Institute of Neuroscience, National Center of Neurology and PsychiatryKodaira, TokyoJapan

Personalised recommendations