Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Nat Commun. 2014 Sep 11;5:4533. doi: 10.1038/ncomms5533.

Abstract

Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK(R211A)) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells
  • Mechanotransduction, Cellular / genetics*
  • Mechanotransduction, Cellular / physiology
  • Mice
  • Mice, Knockout
  • Myocardial Contraction / genetics*
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*

Substances

  • Calcium-Binding Proteins
  • phospholamban
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases