Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart

Sorcin is a 21.6-kDa Ca2+ binding protein of the penta-EF hand family. Several studies have shown that sorcin modulates multiple proteins involved in excitation-contraction (E-C) coupling in the heart, such as the cardiac ryanodine receptor (RyR2), L-type Ca2+ channel, and Na+-Ca2+ exchanger, while it has also been shown to be phosphorylated by cAMP-dependent protein kinase (PKA). To elucidate the effects of sorcin and its PKA-dependent regulation on E-C coupling in the heart, we identified the PKA-phosphorylation site of sorcin, and found that serine178 was preferentially phosphorylated by PKA and dephosphorylated by protein phosphatase-1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulum (SR). In addition, adenovirus-mediated overexpression of sorcin in adult rat cardiomyocytes significantly increased both the rate of decay of the Ca2+ transient and the SR Ca2+ load. An assay of oxalate-facilitated Ca2+ uptake showed that recombinant sorcin increased Ca2+ uptake in a dose-dependent manner. These data suggest that sorcin activates the Ca2+-uptake function in the SR. In UM-X7.1 cardiomyopathic hamster hearts, the relative amount of sorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole-heart homogenates. In failing hearts, PKA-phosphorylated sorcin was markedly increased, as assessed using a back-phosphorylation assay with immunoprecipitated sorcin. Our results suggest that sorcin activates Ca2+-ATPase-mediated Ca2+ uptake and restores SR Ca2+ content, and may play critical roles in compensatory mechanisms in both Ca2+ homeostasis and cardiac dysfunction in failing hearts.