P38α regulates SERCA2a function

Leena Kaikkonen, Johanna Magga, Veli Pekka Ronkainen, Elina Koivisto, Ábel Perjes, J. Kurt Chuprun, Leif Erik Vinge, Teemu Kilpiö, Jani Aro, Johanna Ulvila, Tarja Alakoski, James A. Bibb, Istvan Szokodi, Walter J. Koch, Heikki Ruskoaho, Risto Kerkelä

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38α and by p38α RNAi, but not with dominant negative p38β. Treatment of cardiomyocytes with dominant negative p38α significantly decreased Ca2+-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca2+-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38α enhances PLB phosphorylation and diastolic Ca2+ uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition.

Original languageEnglish (US)
Pages (from-to)86-93
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume67
DOIs
StatePublished - Feb 1 2014

Keywords

  • Cardiac contractility
  • P38
  • Phospholamban
  • SERCA2a

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Kaikkonen, L., Magga, J., Ronkainen, V. P., Koivisto, E., Perjes, Á., Chuprun, J. K., Vinge, L. E., Kilpiö, T., Aro, J., Ulvila, J., Alakoski, T., Bibb, J. A., Szokodi, I., Koch, W. J., Ruskoaho, H., & Kerkelä, R. (2014). P38α regulates SERCA2a function. Journal of Molecular and Cellular Cardiology, 67, 86-93. https://doi.org/10.1016/j.yjmcc.2013.12.005