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, I. Szokodi, Walter J. Koch, Heikki Ruskoaho, Risto Kerkelä

Research output: Contribution to journalArticle

15 Citations (Scopus)

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
Pages (from-to)86-93
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume67
DOIs
Publication statusPublished - Feb 2014

Fingerprint

Cardiac Myocytes
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Phosphorylation
Protein Phosphatase 2
L-Type Calcium Channels
Ryanodine Receptor Calcium Release Channel
p38 Mitogen-Activated Protein Kinases
RNA Interference
Cyclic AMP-Dependent Protein Kinases
phospholamban

Keywords

  • Cardiac contractility
  • P38
  • Phospholamban
  • SERCA2a

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Kaikkonen, L., Magga, J., Ronkainen, V. P., Koivisto, E., Perjes, Á., Chuprun, J. K., ... 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

P38α regulates SERCA2a function. / Kaikkonen, Leena; Magga, Johanna; Ronkainen, Veli Pekka; Koivisto, Elina; Perjes, Ábel; Chuprun, J. Kurt; Vinge, Leif Erik; Kilpiö, Teemu; Aro, Jani; Ulvila, Johanna; Alakoski, Tarja; Bibb, James A.; Szokodi, I.; Koch, Walter J.; Ruskoaho, Heikki; Kerkelä, Risto.

In: Journal of Molecular and Cellular Cardiology, Vol. 67, 02.2014, p. 86-93.

Research output: Contribution to journalArticle

Kaikkonen, L, Magga, J, Ronkainen, VP, Koivisto, E, Perjes, Á, Chuprun, JK, Vinge, LE, Kilpiö, T, Aro, J, Ulvila, J, Alakoski, T, Bibb, JA, Szokodi, I, Koch, WJ, Ruskoaho, H & Kerkelä, R 2014, 'P38α regulates SERCA2a function', Journal of Molecular and Cellular Cardiology, vol. 67, pp. 86-93. https://doi.org/10.1016/j.yjmcc.2013.12.005
Kaikkonen L, Magga J, Ronkainen VP, Koivisto E, Perjes Á, Chuprun JK et al. P38α regulates SERCA2a function. Journal of Molecular and Cellular Cardiology. 2014 Feb;67:86-93. https://doi.org/10.1016/j.yjmcc.2013.12.005
Kaikkonen, Leena ; Magga, Johanna ; Ronkainen, Veli Pekka ; Koivisto, Elina ; Perjes, Ábel ; Chuprun, J. Kurt ; Vinge, Leif Erik ; Kilpiö, Teemu ; Aro, Jani ; Ulvila, Johanna ; Alakoski, Tarja ; Bibb, James A. ; Szokodi, I. ; Koch, Walter J. ; Ruskoaho, Heikki ; Kerkelä, Risto. / P38α regulates SERCA2a function. In: Journal of Molecular and Cellular Cardiology. 2014 ; Vol. 67. pp. 86-93.
@article{bc9ff6094e9c478d8765d1272f4cf339,
title = "P38α regulates SERCA2a function",
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.",
keywords = "Cardiac contractility, P38, Phospholamban, SERCA2a",
author = "Leena Kaikkonen and Johanna Magga and Ronkainen, {Veli Pekka} and Elina Koivisto and {\'A}bel Perjes and Chuprun, {J. Kurt} and Vinge, {Leif Erik} and Teemu Kilpi{\"o} and Jani Aro and Johanna Ulvila and Tarja Alakoski and Bibb, {James A.} and I. Szokodi and Koch, {Walter J.} and Heikki Ruskoaho and Risto Kerkel{\"a}",
year = "2014",
month = "2",
doi = "10.1016/j.yjmcc.2013.12.005",
language = "English",
volume = "67",
pages = "86--93",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - P38α regulates SERCA2a function

AU - Kaikkonen, Leena

AU - Magga, Johanna

AU - Ronkainen, Veli Pekka

AU - Koivisto, Elina

AU - Perjes, Ábel

AU - Chuprun, J. Kurt

AU - Vinge, Leif Erik

AU - Kilpiö, Teemu

AU - Aro, Jani

AU - Ulvila, Johanna

AU - Alakoski, Tarja

AU - Bibb, James A.

AU - Szokodi, I.

AU - Koch, Walter J.

AU - Ruskoaho, Heikki

AU - Kerkelä, Risto

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

KW - Cardiac contractility

KW - P38

KW - Phospholamban

KW - SERCA2a

UR - http://www.scopus.com/inward/record.url?scp=84892888945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892888945&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2013.12.005

DO - 10.1016/j.yjmcc.2013.12.005

M3 - Article

VL - 67

SP - 86

EP - 93

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -