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Am J Physiol Heart Circ Physiol (April 6, 2007). doi:10.1152/ajpheart.00104.2007
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Submitted on January 25, 2007
Accepted on April 1, 2007

Phosphorylation of Human Inhibitor-1 at Ser-67 and/or Thr-75 Attenuates the Stimulatory Effects of Protein Kinase A-Signaling in Cardiac Myocytes

Patricia Rodriguez1, Bryan Mitton1, Persoulla Nicolaou1, Guoli Chen1, and Evangelia G Kranias1*

1 Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, United States

* To whom correspondence should be addressed. E-mail: kraniaeg{at}ucmail.uc.edu.

The depressed function of failing hearts has been partially attributed to increased protein phosphatase-1 through its impaired regulation by inhibitor-1. Phosphorylation of inhibitor-1 at Thr-35 by PKA results in potent inhibition of protein phosphatase-1 activity, while phosphorylation at Ser-67 or Thr-75 by PKC attenuates the inhibitory activity. To examine the functional role of dual site (S67, T75) phosphorylation of inhibitor-1 by PKC, the constitutively phosphorylated Ser-67 (S67D) and/or Thr-75 (T75D) human inhibitor-1 forms were expressed in adult cardiomyocytes. Expression of either single or double phosphorylated inhibitor-1 was associated with similar decreases in cardiac contractility, indicating that maximal inhibition can be elicited by each of these sites alone and their inhibitory effects are not additive. Notably, activation of the cAMP pathway could only partially reverse the depressed contractile parameters. Accordingly, the protein phosphatase-1 activity remained elevated, phosphorylation of phospholamban at Ser-16 was decreased, and the EC50 values of the sarcoplasmic reticulum calcium transport system were higher compared to controls. Thus, phosphorylation of Ser-67 and/or Thr-75 in inhibitor-1 may mitigate the stimulatory effects of the cAMP pathway, resulting in compromised cardiac function.




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