Details

Autor(en) / Beteiligte

• Cazorla, Olivier
• Lucas, Alexandre
• Poirier, Florence
• Lacampagne, Alain
• Lezoualc'h, Frank
• Beavo, Joseph A.

Titel

The cAMP Binding Protein Epac Regulates Cardiac Myofilament Function

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-08, Vol.106 (33), p.14144-14149

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2009

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• In the heart, cAMP is a key regulator of excitation–contraction coupling and its biological effects are mainly associated with the activity of protein kinase A (PKA). The aim of this study was to investigate the contribution of the cAMP-binding protein Epac (Exchange protein directly activated by cAMP) in the regulation of the contractile properties of rat ventricular cardiac myocytes. We report that both PKA and Epac increased cardiac sarcomere contraction but through opposite mechanisms. Differently from PKA, selective Epac activation by the cAMP analog 8-(4-chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT) reduced Ca²⁺ transient amplitude and increased cell shortening in intact cardiomyocytes and myofilament Ca²⁺ sensitivity in permeabilized cardiomyocytes. Moreover, ventricular myocytes, which were infected in vivo with a constitutively active form of Epac, showed enhanced myofilament Ca²⁺ sensitivity compared to control cells infected with green fluorescent protein (GFP) alone. At the molecular level, Epac increased phosphorylation of 2 key sarcomeric proteins, cardiac Troponin I (cTnl) and cardiac Myosin Binding Protein-C (cMyBP-C). The effects of Epac activation on myofilament Ca²⁺ sensitivity and on cTnl and cMyBP-C phosphorylation were independent of PKA and were blocked by protein kinase C (PKC) and Ca²⁺ calmodulin kinase II (CaMKII) inhibitors. Altogether these findings identify Epac as a new regulator of myofilament function.