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Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome

Evangelia G Kranias1, Roger J Hajjar

  • 1Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. Litsa.Kranias@uc.edu

Circulation Research
|June 9, 2012
PubMed

Insights

Heart failure impairs cardiac contractility by affecting calcium handling. New research reveals complex regulation of the SERCA2 pump by phospholamban and other proteins, offering novel therapeutic targets.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Heart disease is a leading cause of death, with heart failure characterized by impaired contractile function.
  • Current therapies address symptoms, not underlying subcellular mechanisms of heart failure.
  • Impaired calcium sequestration into the sarcoplasmic reticulum (SR) is a hallmark of failing hearts.

Purpose of the Study:

  • To review the regulatory mechanisms of cardiac contractility involving the SERCA/PLN complex.
  • To explore new therapeutic strategies targeting this complex for heart failure treatment.

Main Methods:

  • Literature review of studies on cardiac calcium handling and SERCA2 regulation.
  • Analysis of the roles of phospholamban (PLN) and newly identified regulatory proteins.
  • Discussion of potential small molecule and gene transfer therapies.

Main Results:

  • The SERCA2 pump's activity is regulated by phospholamban (PLN), with phosphorylation relieving inhibition.
  • New regulators of SERCA activity include SUMO, S100, and histidine-rich Ca-binding protein.
  • PLN activity is further modulated by inhibitor-1 of protein phosphatase 1 and small heat shock protein 20.

Conclusions:

  • Cardiac contractility is regulated by a multimeric SERCA/PLN ensemble.
  • Understanding these complex regulatory mechanisms opens avenues for novel heart failure therapeutics.
  • Targeting the SERCA/PLN complex with small molecules or gene transfer shows therapeutic potential.

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