p38α regulates SERCA2a function

J Mol Cell Cardiol. 2014 Feb;67:86-93. doi: 10.1016/j.yjmcc.2013.12.005. Epub 2013 Dec 17.

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 Ca(2+)-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca(2+)-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 Ca(2+) uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition.

Keywords: AMVM; ARVM; Cardiac contractility; ET-1; G protein coupled receptor kinase; GRK; I-1; MAPK; NRVM; OA; PLB; PP1; PP2A; Phospholamban; SERCA2a; adult mouse ventricular myocyte; adult rat ventricular myocyte; dn; dominant negative; endothelin-1; inhibitor-1; mitogen-activated protein kinase; neonatal rat ventricular myocyte; okadaic acid; p38; phospholamban; protein phosphatase-1; protein phosphatase-2A; sarco/endoplasmic reticulum Ca(2+) ATPase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism
  • Enzyme Activation / drug effects
  • Muscle Contraction / physiology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology*
  • Phosphorylation
  • RNA Interference
  • Rats
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / pharmacology

Substances

  • Calcium-Binding Proteins
  • phospholamban
  • p38 Mitogen-Activated Protein Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium