Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart.
Sorcin is a 21.6-kDa Ca(2+) 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 Ca(2+) channel, and Na(+)-Ca(2+) 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 Ca(2+) transient and the SR Ca(2+) load. An assay of oxalate-facilitated Ca(2+) uptake showed that recombinant sorcin increased Ca(2+) uptake in a dose-dependent manner. These data suggest that sorcin activates the Ca(2+)-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 Ca(2+)-ATPase-mediated Ca(2+) uptake and restores SR Ca(2+) content, and may play critical roles in compensatory mechanisms in both Ca(2+) homeostasis and cardiac dysfunction in failing hearts.
Matsumoto
Tomo
T
Division of Cardiovascular Medicine, Department of Medical Bioregulation, Yamaguchi University Graduate, School of Medicine, 1-1-1 Minami-kogushi, Ube Yamaguchi 755-8505, Japan.
Hisamatsu
Yuji
Y
Ohkusa
Tomoko
T
Inoue
Noriko
N
Sato
Takashi
T
Suzuki
Shinsuke
S
Ikeda
Yasuhiro
Y
Matsuzaki
Masunori
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008647:Mesocricetus; D016297:Mutagenesis, Site-Directed; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium