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Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3

  • Cardiovascular Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Glycogen synthase kinase 3 (GSK3) plays a decisive role in the regulation of multiple functions. GSK3 is phosphorylated and its activity inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which are in turn activated by growth factors through phosphoinositide (PI) 3 kinase signaling. PI3/PKB/Akt/SGK-dependent inhibition of GSK3 is disrupted in gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3α,ß (gsk3 KI) where the serine of the PKB/SGK phosphorylation site has been replaced by alanine. Recent experiments revealed that blood pressure is significantly higher in those mice than in wild type mice (gsk3 WT). The present study was performed to elucidate the underlying cause. Blood pressure was determined with the tail cuff method, heart rate by ECG measurements, catecholamine concentrations by ELISA, and vanillylmandelic acid by high pressure liquid chromatography. As a result, blood pressure and heart rate were significantly higher in gsk3 KI than in gsk3 WT mice. The α-adrenergic blocker prazosin (1 μg/g body weight, b.w.) and the ganglion blocker hexamethonium (40 μg/g b.w.) decreased blood pressure to a larger extent in gsk3 KI than in gsk3 WT mice and virtually abrogated the difference between genotypes. Similarly, the β-adrenergic blocker atenolol (5 μg/g b.w.) decreased the heart rate to a larger extent in gsk3 KI than in gsk3 WT mice and again dissipated the difference of heart rate between genotypes. Plasma epinephrine and norepinephrine concentrations, as well as urinary excretion of vanillylmandelic acid, were significantly higher in gsk3 KI than in gsk3 WT mice. The observations reveal a completely novel function of PKB/Akt/SGK-dependent GSK3 signaling, i.e., regulation of catecholamine release.

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Acknowledgments

The authors acknowledge the technical assistance of E. Faber and the meticulous preparation of the manuscript by S. Ruebe and L. Subasic. This study was supported by the Deutsche Forschungsgemeinschaft (GK 1302).

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Balasaheb Siraskar, Jakob Völkl, Mohamed Siyabeldin E. Ahmed, Michael Hierlmeier, Shuchen Gu, Evi Schmid, Christina Leibrock, Michael Föller & Florian Lang

  2. Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany

    Undine E. Lang

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  1. Balasaheb Siraskar
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  2. Jakob Völkl
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Correspondence to Florian Lang.

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Balasaheb Siraskar and Jakob Völkl contributed equally and thus share first authorship.

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Siraskar, B., Völkl, J., Ahmed, M.S.E. et al. Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3. Pflugers Arch - Eur J Physiol 462, 811–819 (2011). https://doi.org/10.1007/s00424-011-1006-6

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  • DOI: https://doi.org/10.1007/s00424-011-1006-6

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