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PKC-alpha regulates cardiac contractility and propensity toward heart failure.

The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.

Pubmed ID: 14966518


  • Braz JC
  • Gregory K
  • Pathak A
  • Zhao W
  • Sahin B
  • Klevitsky R
  • Kimball TF
  • Lorenz JN
  • Nairn AC
  • Liggett SB
  • Bodi I
  • Wang S
  • Schwartz A
  • Lakatta EG
  • DePaoli-Roach AA
  • Robbins J
  • Hewett TE
  • Bibb JA
  • Westfall MV
  • Kranias EG
  • Molkentin JD


Nature medicine

Publication Data

March 1, 2004

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 5T32 HL07382

Mesh Terms

  • Animals
  • Calcium
  • Calcium-Binding Proteins
  • Calcium-Transporting ATPases
  • Calsequestrin
  • Cardiac Output, Low
  • Cardiomyopathies
  • Isoenzymes
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocardium
  • Myocytes, Cardiac
  • Phosphoprotein Phosphatases
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Protein Phosphatase 1
  • Rats
  • Risk Factors
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases