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Phosphorylation of phospholamban and troponin I through 5-HT4 receptors in the isolated human atrium

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Abstract

We studied the mRNA expression and function of 5-hydroxytryptamine (5-HT) receptors as well as their signal transduction in right atrial tissue from patients undergoing cardiac surgery and right ventricular tissue from human donor hearts. In isolated, electrically driven strips from human right atrium, 5-HT exerted concentration-dependent positive inotropic effects (EC50 value = 0.10 ± 0.01 μM) and hastened relaxation (positive lusitropic effect). The 5-HT4 receptor antagonists SB203186 or GR125487 antagonised these effects. 5-HT (2 μM) increased the content of cyclic adenosine monophosphate (cAMP) from 6.86 ± 1.36 to 19.1 ± 2.45 pmol/mg protein (n = 6, p < 0.05) but did not alter the tissue content of inositol-1,4,5-trisphosphate (IP3). With reverse transcription polymerase chain reaction, mRNAs coding for the 5-HT4 receptor splice variants 5-HT4(a), 5-HT4(b) and 5-HT4(c) were detected in human right atrium and right ventricle. 5-HT2A mRNA only was measurable in human atrium. Expression level of total 5-HT4 receptor mRNA in the right ventricle amounted to 41% (n = 5–8) of that in the right atrium. 5-HT (2 μM) increased the atrial phosphorylation states of phospholamban to 168% at serine-16 and to 150% at threonine-17 (n = 4; p < 0.05) and of the inhibitory subunit of troponin to 150% (n = 6; p < 0.05). In conclusion, the positive inotropic and lusitropic effects of 5-HT in electrically driven human right atria are mediated via 5-HT4 receptors. These effects are accompanied by and probably due to an increase in cAMP content and the subsequent elevation of the phosphorylation state of Ca2+ regulatory proteins.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft. We thank Dr. G.S. Bodor (Denver) for the gift of TnI 1E11.3 and 2F6.6.51 antibodies. The work contains parts of the doctoral thesis of Freerk Ole Remmers. The technical assistance of S. Reber is greatly appreciated.

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 4, 06112, Halle, Germany

    Ulrich Gergs & Joachim Neumann

  2. Klinik für Herz- und Thoraxchirurgie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097, Halle, Germany

    Andreas Simm & Rolf-Edgar Silber

  3. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, 20246, Hamburg, Germany

    Freerk Ole Remmers

  4. Klinische Pharmazie und Pharmakotherapie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany

    Stephanie Läer

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  1. Ulrich Gergs
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  2. Joachim Neumann
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  3. Andreas Simm
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  4. Rolf-Edgar Silber
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  5. Freerk Ole Remmers
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  6. Stephanie Läer
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Correspondence to Ulrich Gergs.

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Gergs, U., Neumann, J., Simm, A. et al. Phosphorylation of phospholamban and troponin I through 5-HT4 receptors in the isolated human atrium. Naunyn-Schmied Arch Pharmacol 379, 349–359 (2009). https://doi.org/10.1007/s00210-008-0371-y

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