Skip to main content
Log in

On the presence of serotonin in mammalian cardiomyocytes

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Pleiotropic effects of serotonin (5-HT) in the cardiovascular system are well documented. However, it remains to be elucidated, whether 5-HT is present in adult mammalian cardiomyocytes. To address this issue, we investigated the levels of 5-HT in blood, plasma, platelets, cardiac tissue, and cardiomyocytes from adult mice and for comparison in human right atrial tissue. Immunohistochemically, 5-HT was hardly found in mouse cardiac tissue, but small amounts could be detected in renal preparations, whereas adrenal preparations revealed a strong positive immunoreaction for 5-HT. Using a sensitive HPLC detection system, 5-HT was also detectable in the mouse heart and human atrium. Furthermore, we could identify 5-HT in isolated cardiomyocytes from adult mice. These findings were supported by detection of the activity of 5-HT-forming enzymes—tryptophan hydroxylase and aromatic l-amino acid decarboxylase—in isolated cardiomyocytes from adult mice and by inhibition of these enzymes with p-chlorophenylalanine and 3-hydroxybenzyl hydrazine. Addition of the first intermediate of 5-HT generation, that is 5-hydroxytryptophan, enhanced the 5-HT level and inhibition of monoamine oxidase by tranylcypromine further increased the level of 5-HT. Our findings reveal the presence and synthesis of 5-HT in cardiomyocytes of the mammalian heart implying that 5-HT may play an autocrine and/or paracrine role in the heart.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Verbeuren T (1990) The distribution and biochemistry of 5-HT in the cardiovascular system. Kluver Academic Press, Dordrecht, pp 3–13

    Google Scholar 

  2. Verbeuren T (1992) Distribution, synthesis, metabolism, release, uptake, and passage across body membranes in cardiovascular tissues including blood-brain barrier. Raven Press, New York, pp 29–39

    Google Scholar 

  3. Kaumann AJ (1994) Do human atrial 5-HT4 receptors mediate arrhythmias? Trends Pharmacol Sci 15:451–455

    Article  PubMed  CAS  Google Scholar 

  4. Robiolio PA, Rigolin VH, Wilson JS, Harrison JK, Sanders LL, Bashore TM, Feldman JM (1995) Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 92:790–795

    PubMed  CAS  Google Scholar 

  5. Kaumann AJ, Levy FO (2006) 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 111:674–706

    Article  PubMed  CAS  Google Scholar 

  6. Yavarone MS, Shuey DL, Tamir H, Sadler TW, Lauder JM (1993) Serotonin and cardiac morphogenesis in the mouse embryo. Teratology 47:573–584

    Article  PubMed  CAS  Google Scholar 

  7. Nebigil CG, Choi DS, Dierich A, Hickel P, Le Meur M, Messaddeq N, Launay JM, Maroteaux L (2000) Serotonin 2B receptor is required for heart development. Proc Natl Acad Sci USA 97:9508–9513

    Article  PubMed  CAS  Google Scholar 

  8. Nebigil CG, Maroteaux L (2001) A novel role for serotonin in heart. Trends Cardiovasc Med 11:329–335

    Article  PubMed  CAS  Google Scholar 

  9. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203

    PubMed  CAS  Google Scholar 

  10. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554

    Article  PubMed  CAS  Google Scholar 

  11. Laer S, Remmers FO, Scholz H, Stein B, Muller FU, Neumann J (1998) Receptor mechanisms involved in the 5-HT-induced inotropic action in the rat isolated atrium. Br J Pharmacol 123:1182–1188

    Article  PubMed  CAS  Google Scholar 

  12. Tramontana M, Giuliani S, Del Bianco E, Lecci A, Maggi CA, Evangelista S, Geppetti P (1993) Effects of capsaicin and 5-HT3 antagonists on 5-hydroxytryptamine-evoked release of calcitonin gene-related peptide in the guinea-pig heart. Br J Pharmacol 108:431–435

    PubMed  CAS  Google Scholar 

  13. Du XY, Schoemaker RG, Bos E, Saxena PR (1994) Different pharmacological responses of atrium and ventricle: studies with human cardiac tissue. Eur J Pharmacol 259:173–180

    Article  PubMed  CAS  Google Scholar 

  14. Gergs U, Neumann J, Simm A, Silber RE, Remmers FO, Laer S (2009) Phosphorylation of phospholamban and troponin I through 5-HT(4) receptors in the isolated human atrium. Naunyn Schmiedebergs Arch Pharmacol 379:349–359

    Article  PubMed  CAS  Google Scholar 

  15. Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ (1990) A 5-hydroxytryptamine receptor in human atrium. Br J Pharmacol 100:879–885

    PubMed  CAS  Google Scholar 

  16. Qvigstad E, Brattelid T, Sjaastad I, Andressen KW, Krobert KA, Birkeland JA, Sejersted OM, Kaumann AJ, Skomedal T, Osnes JB, Levy FO (2005) Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure. Cardiovasc Res 65:869–878

    Article  PubMed  CAS  Google Scholar 

  17. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76

    Article  PubMed  CAS  Google Scholar 

  18. Popova NK (2006) From genes to aggressive behavior: the role of serotonergic system. BioEssays 28:495–503

    Article  PubMed  CAS  Google Scholar 

  19. Lee SL, Fanburg BL (1986) Serotonin uptake by bovine pulmonary artery endothelial cells in culture. I. Characterization. Am J Physiol 250:C761–C765

    PubMed  CAS  Google Scholar 

  20. Mekontso-Dessap A, Brouri F, Pascal O, Lechat P, Hanoun N, Lanfumey L, Seif I, Benhaiem-Sigaux N, Kirsch M, Hamon M, Adnot S, Eddahibi S (2006) Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation 113:81–89

    Article  PubMed  CAS  Google Scholar 

  21. Yusuf S, Al-Saady N, Camm AJ (2003) 5-hydroxytryptamine and atrial fibrillation: how significant is this piece in the puzzle? J Cardiovasc Electrophysiol 14:209–214

    Article  PubMed  Google Scholar 

  22. Ikeda K, Tojo K, Otsubo C, Udagawa T, Kumazawa K, Ishikawa M, Tokudome G, Hosoya T, Tajima N, Claycomb WC, Nakao K, Kawamura M (2005) 5-hydroxytryptamine synthesis in HL-1 cells and neonatal rat cardiocytes. Biochem Biophys Res Commun 328:522–525

    Article  PubMed  CAS  Google Scholar 

  23. Pönicke K, Gergs U, Hauptmann S, Buchwalow IB, Neumann J (2008) Release of 5-hydroxytryptamine from heart and isolated adult mice cardiomyocytes. Naunyn Schmiedebergs Arch Pharmacol 377(Suppl 1):57

    Google Scholar 

  24. Kirchhefer U, Neumann J, Baba HA, Begrow F, Reinke U, Schmitz W, Kobayashi YM, Jones LR (2001) Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1. J Biol Chem 276:4142–4149

    Article  PubMed  CAS  Google Scholar 

  25. Buchwalow IB, Podzuweit T, Bocker W, Samoilova VE, Thomas S, Wellner M, Baba HA, Robenek H, Schnekenburger J, Lerch MM (2002) Vascular smooth muscle and nitric oxide synthase. FASEB J 16:500–508

    Article  PubMed  CAS  Google Scholar 

  26. Buchwalow IB, Podzuweit T, Samoilova VE, Wellner M, Haller H, Grote S, Aleth S, Boecker W, Schmitz W, Neumann J (2004) An in situ evidence for autocrine function of NO in the vasculature. Nitric Oxide 10:203–212

    Article  PubMed  CAS  Google Scholar 

  27. Lairez O, Calise D, Bianchi P, Ordener C, Spreux-Varoquaux O, Guilbeau-Frugier C, Escourrou G, Seif I, Roncalli J, Pizzinat N, Galinier M, Parini A, Mialet-Perez J (2009) Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload. J Mol Cell Cardiol 46:587–595

    Article  PubMed  CAS  Google Scholar 

  28. Izikki M, Hanoun N, Marcos E, Savale L, Barlier-Mur AM, Saurini F, Eddahibi S, Hamon M, Adnot S (2007) Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 293:L1045–L1052

    Article  PubMed  CAS  Google Scholar 

  29. Kubovcakova L, Krizanova O, Kvetnansky R (2004) Identification of the aromatic l-amino acid decarboxylase gene expression in various mice tissues and its modulation by immobilization stress in stellate ganglia. Neuroscience 126:375–380

    Article  PubMed  CAS  Google Scholar 

  30. Lopez-Contreras AJ, Galindo JD, Lopez-Garcia C, Castells MT, Cremades A, Penafiel R (2008) Opposite sexual dimorphism of 3,4-dihydroxyphenylalanine decarboxylase in the kidney and small intestine of mice. J Endocrinol 196:615–624

    Article  PubMed  CAS  Google Scholar 

  31. Ni W, Watts SW (2006) 5-hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT). Clin Exp Pharmacol Physiol 33:575–583

    Article  PubMed  CAS  Google Scholar 

  32. Sole MJ, Shum A, Van Loon GR (1979) Serotonin metabolism in the normal and failing hamster heart. Circ Res 45:629–634

    PubMed  CAS  Google Scholar 

  33. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G (2003) Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 100:13525–13530

    Article  PubMed  CAS  Google Scholar 

  34. Vaniotis G, Del Duca D, Trieu P, Rohlicek CV, Hébert TE, Allen BG (2011) Nuclear β-adrenergic receptors modulate gene expression in adult rat heart. Cell Signal 23:89–98

    Article  PubMed  CAS  Google Scholar 

  35. Kelly CJ, Johnson TC (1978) Effects of p-chlorophenylalanine and alpha-methylphenylalanine on amino acid uptake and protein synthesis in mouse neuroblastoma cells. Biochem J 174:931–938

    PubMed  CAS  Google Scholar 

  36. Monassier L, Laplante MA, Ayadi T, Doly S, Maroteaux L (2010) Contribution of gene-modified mice and rats to our understanding of the cardiovascular pharmacology of serotonin. Pharmacol Ther 128:559–567

    Article  PubMed  CAS  Google Scholar 

  37. Gergs U, Baumann M, Böckler A, Buchwalow IB, Ebelt H, Fabritz L, Hauptmann S, Keller N, Kirchhof P, Klöckner U, Pönicke K, Rueckschloss U, Schmitz W, Werner F, Neumann J (2010) Cardiac overexpression of the human 5-HT4 receptor in mice. Am J Physiol Heart Circ Physiol 299:H788–H798

    Article  PubMed  CAS  Google Scholar 

  38. Ringvall M, Rönnberg E, Wernersson S, Duelli A, Henningsson F, Abrink M, García-Faroldi G, Fajardo I, Pejler G (2008) Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan. J Allergy Clin Immunol 121:1020–1026

    Article  PubMed  CAS  Google Scholar 

  39. Correa-Araujo R, Oliveira JS, Ricciardi Cruz A (1991) Cardiac levels of norepinephrine, dopamine, serotonin and histamine in Chagas’ disease. Int J Cardiol 31:329–336

    Article  PubMed  CAS  Google Scholar 

  40. Mialet-Perez J, Bianchi P, Kunduzova O, Parini A (2007) New insights on receptor-dependent and monoamine oxidase-dependent effects of serotonin in the heart. J Neural Transm 114:823–827

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The technical assistance of A. Spiess-Dunemann and I. Adler is greatly appreciated. This study was supported by the Deutsche Forschungsgemeinschaft (DFG).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joachim Neumann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pönicke, K., Gergs, U., Buchwalow, I.B. et al. On the presence of serotonin in mammalian cardiomyocytes. Mol Cell Biochem 365, 301–312 (2012). https://doi.org/10.1007/s11010-012-1270-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1270-6

Keywords

Navigation