PMID:14966518

Citation	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 and Molkentin, JD (2004) PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat. Med. 10:248-54
Abstract	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.
Links	PubMed Online version:10.1038/nm1000
Keywords	Animals; Calcium/metabolism; Calcium-Binding Proteins/metabolism; Calcium-Transporting ATPases/metabolism; Calsequestrin/metabolism; Cardiac Output, Low/physiopathology; Cardiomyopathies/metabolism; Isoenzymes/genetics; Isoenzymes/metabolism; Mice; Mice, Transgenic; Myocardial Contraction/physiology; Myocardium/cytology; Myocardium/metabolism; Myocytes, Cardiac/cytology; Myocytes, Cardiac/metabolism; Phosphoprotein Phosphatases/antagonists & inhibitors; Phosphoprotein Phosphatases/metabolism; Protein Kinase C/genetics; Protein Kinase C/metabolism; Protein Kinase C-alpha; Protein Phosphatase 1; Rats; Risk Factors; Sarcoplasmic Reticulum Calcium-Transporting ATPases
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.