Skip to main content
Log in

Cyclic GMP generation mediated by 5-HT-2 receptors via nitric oxide-dependent pathway and its effect on the desensitization of 5-HT-2 receptors in C6 glioma cells

  • Full Papers
  • Published:
Journal of Neural Transmission / General Section JNT Aims and scope Submit manuscript

Summary

Serotonin (5-HT)-2 receptor-mediated cGMP generation was investigated in comparison with calcium (Ca2+) mobilization in C6 glioma cells. 5-HT enhanced cGMP generation, and risperidone and ketanserin potently blocked the response. These results indicate that 5-HT-2 receptors are responsible for the cGMP generation. 5-HT-induced cGMP production was completely abolished by BAPTA, an intracellular Ca2+ chelating agent, or Ng-monomethyl-L-arginine (NMMA), a nitric oxide synthase (NOS) inhibitor, suggesting that 5-HT-induced cGMP generation was through nitric oxide (NO)-dependent pathway. 5-HT (10 μM)-elicited Ca2+ mobilization and cGMP generation were reduced to 40 and 15 % after pretreatment with 10 μM 5-HT for 4 hours. NMMA did not modify 5-HT-induced desensitization of either Ca2+ mobilization or cGMP generation, suggesting that NO pathway is independent of the desensitization. The present study has demonstrated the nature of 5-HT-2 receptormediated cGMP generation in C6 glioma cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Agullo L, Garcia A (1991) Norepinephrine increases cyclic GMP in astrocytes by a mechanism dependent on nitric oxide synthesis. Eur J Pharmacol 206: 343–346

    Google Scholar 

  • Apud JA, Grayson DR, De Erausquin E, Costa E (1992) Pharmacological characterization of regulation of phosphoinositide metabolism by recombinant 5-HT2 receptors of the rat. Neuropharmacology 31: 1–8

    Google Scholar 

  • Bottenstein JE, de Vellis J (1978) Regulation of cyclic GMP, cyclic AMP and lactate dehydrogenase by putative neurotransmitters in the C6 rat glioma cell line. Life Sci 23: 821–834

    Google Scholar 

  • Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86: 9030–9033

    Google Scholar 

  • Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351: 714–718

    Google Scholar 

  • Dillon-Carter O, Chuang DM (1989) Homologous desensitization of muscarinic cholinergic, histaminergic, adrenergic, and serotonergic receptors coupled to phospholipase C in cerebellar granule cells. J Neurochem 52: 598–603

    Google Scholar 

  • Galea E, Feinstein DL, Reis DJ (1992) Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci USA 89: 10945–10949

    Google Scholar 

  • Galione A, White A, Willmott N, Turner M, Potter BVL, Watson SP (1993) cGMP mobilizes intracellular Ca2+ in sea urchin eggs by stimulating cyclic ADP-ribose synthesis. Nature 365: 456–459

    Google Scholar 

  • Garthwaite J, Garthwaite G, Palmer RMJ, Moncada S (1989) NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol Mol Pharmacol Sect 172: 413–416

    Google Scholar 

  • Gopalakrishna R, Chen ZH, Gundimeda U (1993) Nitric oxide and nitric oxide-generating agents induce a reversible inactivation of protein kinase C activity and phorbol ester binding. J Biol Chem 268: 27180–27185

    Google Scholar 

  • Guevara-Guzman R, Emson PC, Kendrick KM (1994) Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J Neurochem 62: 807–810

    Google Scholar 

  • Haby C, Lisovoski F, Aunis D, Zwiller J (1994) Stimulation of the cyclic GMP pathway by NO induces expression of the immediate early genes c-fos and junB in PC12 cells. J Neurochem 62: 496–501

    Google Scholar 

  • Hirsch DB, Steiner JP, Dawson TM, Mammen A, Hayek E, Snyder SH (1993) Neurotransmitter release regulated by nitric oxide in PC-12 cells and brain synaptosomes. Curr Biol 3: 749–754

    Google Scholar 

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

    Google Scholar 

  • Ivins KJ, Molinoff PB (1991) Desensitization and down-regulation of 5-HT-2 receptors in P11 cells. J Pharmacol Exp Ther 259: 423–429

    Google Scholar 

  • Kagaya A, Mikuni M, Kusumi I, Yamamoto H, Takahashi K (1990) Serotonin-induced acute desensitization of serotonin2 receptors in human platelets via a mechanism involving protein kinase C. J Pharmacol Exp Ther 255: 305–311

    Google Scholar 

  • Kagaya A, Mikuni M, Muraoka S, Saitoh K, Ogawa T, Shinno H, Yamawaki S, Takahashi K (1993) Homologous desensitization of serotonin 5-HT2 receptor-stimulated intracellular calcium mobilization in C6BU-1 glioma cells via a mechanism involving a calmodulin pathway. J Neurochem 61: 1050–1056

    Google Scholar 

  • Knowles RG, Palacios M, Palmer RMJ, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 86: 5159–5162

    Google Scholar 

  • Kusumi I, Koyama T, Yamashita I (1991) Serotonin-stimulated Ca2+ response is increased in the blood platelets of depressed patients. Biol Psychiatry 30: 310–312

    Google Scholar 

  • Lamas S, Marsden PA, Li GK, Tempst P, Michel T (1992) Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 89: 6348–6352

    Google Scholar 

  • Leysen JE, Janssen MMF, Gommeren W, Wynants J, Pauwels PJ, Janssen PAJ (1992) In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. Mol Pharmacol 41: 494–508

    Google Scholar 

  • Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275

    Google Scholar 

  • Lyons CR, Orloff GJ, Cunningham JM (1992) Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 267: 6370–6374

    Google Scholar 

  • Marsden PA, Schappert KT, Chen HS, Flowers M, Sundell CL, Wilcox JN, Lamas S, Michel T (1992) Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 307: 287–293

    Google Scholar 

  • Meltzer HY, Umberkoman-Wiita B, Robertson A, Tricou BJ, Lowy M, Perline R (1984) Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. 1. Enhanced response in depression and mania. Arch Gen Psychiatry 41: 366–374

    Google Scholar 

  • Mikuni M, Kusumi I, Kagaya A, Kuroda Y, Mori H, Takahashi K (1991) Increased 5-HT-2 receptor function as measured by serotonin-stimulated phosphoinositide hydrolysis in platelets of depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 15: 49–61

    Google Scholar 

  • Mikuni M, Kagaya A, Takahashi K, Meltzer HY (1992) Serotonin but not norepinephrineinduced calcium mobilization is enhanced in platelets of affective disorders. Psycho-pharmacology 106: 311–314

    Google Scholar 

  • Minc-Golomb D, Schwartz JP (1992) Transcription of the brain nitric oxide synthase gene in neural cell cultures. Soc Neurosci 18: 1004

    Google Scholar 

  • Munoz-Fernandez MA, Fresno M (1993) Involvement of nitric oxide on the cytokine induced growth of glial cell. Biochem Biophys Res Commun 194: 319–325

    Google Scholar 

  • Muraoka S, Mikuni M, Kagaya A, Saitoh K, Takahashi K (1993) Dexamethasone potentiates serotonin-2 receptor-mediated intracellular Ca2+ mobilization in C6 glioma cells. Neuroendocrinology 57: 322–329

    Google Scholar 

  • Murphy S, Minor Jr RL, Welk G, Harrison DG (1990) Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide. J Neurochem 55: 349–351

    Google Scholar 

  • Murphy S, Simmons ML, Agullo L, Garcia A, Feinstein DL, Galea E, Reis D, Minc-Golomb D, Schwartz J (1993) Synthesis of nitric oxide in CNS glial cells. Trends Neurosci 16: 323–328

    Google Scholar 

  • Ogura A, Ozaki K, Kudo Y, Amano T (1986) Cytosolic calcium elevation and cGMP production induced by serotonin in a clonal cell of glial origin. J Neurosci 6: 2489–2494

    Google Scholar 

  • Pauwels PJ, Van Gompel P, Leysen JE (1990) Rapid desensitization and resensitization of 5-HT-2 receptor mediated phosphatidyl inositol hydrolysis by serotonin agonists in quiescent calf aortic smooth muscle cells. Life Sci 47: 2009–2019

    Google Scholar 

  • Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1c receptors. J Pharmacol Exp Ther 260: 1361–1365

    Google Scholar 

  • Sibley DR, Benovic JL, Caron MG, Lefkowitz RJ (1987) Regulation of transmembrane signaling by receptor phosphorylation. Cell 48: 913–922

    Google Scholar 

  • Simmons ML, Murphy S (1992) Induction of nitric oxide synthase in glial cells. J Neurochem 59: 897–905

    Google Scholar 

  • Simmons ML, Murphy S (1993) Cytokines regulate L-arginine-dependent cyclic GMP production in rat glial cell. Eur J Neurosci 5: 825–831

    Google Scholar 

  • Tanaka T, Saito H, Matsuki N (1993) Endogenous nitric oxide inhibits NMDA- and kainate-responses by a negative feedback system in rat hippocampal neurons. Brain Res 631: 72–76

    Google Scholar 

  • Tohda M, Nomura Y (1990) Serotonin stimulates both cytosolic and membrane-bound guanylate cyclase in NG108-15 cells. J Neurochem 55: 1800–1805

    Google Scholar 

  • Vigne P, Damais C, Frelin C (1993) IL-1 and TNF α induce cGMP formation in C6 astrocytoma cells via the nitridergic pathway. Brain Res 606: 332–334

    Google Scholar 

  • Xie Q, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C (1992) Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256: 225–228

    Google Scholar 

  • Yamawaki S, Sugihara J, Kato T, Hayakawa H, Shimizu M (1990) 5-HT2 receptor-mediated Ca2+ increase in platelets of bipolar disorder. 17th CINP Congress (Abstracts, p 29)

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kagaya, A., Motohashi, N., Kugaya, A. et al. Cyclic GMP generation mediated by 5-HT-2 receptors via nitric oxide-dependent pathway and its effect on the desensitization of 5-HT-2 receptors in C6 glioma cells. J. Neural Transmission 100, 27–38 (1995). https://doi.org/10.1007/BF01276863

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01276863

Keywords

Navigation