Ischemia induces phospholamban dephosphorylation via activation of calcineurin, PKC-α, and protein phosphatase 1, thereby inducing calcium overload in reperfusion

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Shintani-Ishida, Kaori¹  Yoshida, Ken-ichi¹ 

[1] Univ Tokyo, Grad Sch Med, Dept Forens Med, Tokyo, Japan

关键词: Phospholamban;    Calcineurin;    Ischemia;    Calcium;    Protein kinase C;   

DOI  :  10.1016/j.bbadis.2011.03.014

来源: Elsevier

【 摘 要 】

Cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) promotes Ca2+ uptake in the SR. Dephosphorylated phospholamban (PLB) inhibits SERCA2a activity. We found a distinct dephosphorylation of PLB at Thr(17) and Ser(16) after 20-30 min of ischemia produced by coronary artery occlusion in rats. The aim of the study was to investigate how PLB is dephosphorylated in ischemia and to determine whether PLB dephosphorylation causes myocardial hypercontraction and calpain activation through Ca2+ overload in reperfusion. Protein inhibitor-1 (1-1) specifically inhibits protein phosphatase 1 (PP1), the predominant PLB phosphatase in heart. A Ca2+-dependent phosphatase calcineurin may also induce PLB dephosphorylation. Ischemia for 30 min induced PKC-alpha translocation, resulting in inactivation of 1-1 through PKC-alpha-dependent phosphorylation at Ser(67). The PP1 activation following 1-1 inactivation was thought to induce PLB dephosphorylation in ischemia. Ischemia for 30 min activated calcineurin, and pretreatment with a calcineurin inhibitor, cyclosporine A (CsA), inhibited PKC-alpha translocation, 1-1 phosphorylation at Ser67, and PLB dephosphorylation in ischemia. Reperfusion for 5 min following 30 min of ischemia induced spreading of contraction bands (CBs) and proteolysis of fodrin by calpain. Both CsA and an anti-PLB antibody that inhibits binding of PLB to SERCA2a reduced the CB area and fodrin breakdown after reperfusion. These results reveal a novel pathway via which ischemia induces calcineurin-dependent activation of PKC-alpha, inactivation of 1-1 through PKC-alpha-dependent phosphorylation at Ser67, and PP1-dependent PLB dephosphorylation. The pathway contributes to the spreading of CBs and calpain activation through Ca2+ overload in early reperfusion. (C) 2011 Elsevier B.V. All rights reserved.

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