Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA2a) activity and impairs cardiac function in mice

• DOI: 10.1073/pnas.0402596101
• Publication Date: 2004-06-17T00:34:16Z
• Authors: Michio Asahi; Kinya Otsu; Hiroyuki Nakayama; Shungo Hikoso; Toshihiro Takeda; Anthony O. Gramolini; Maria G. Trivieri; Gavin Y. Oudit; Takashi Morita; Yoichiro Kusakari; Shuta Hirano; Kenichi Hongo; Shinichi Hirotani; Osamu Yamaguchi; Alan Peterson; Peter H. Backx; Satoshi Kurihara; Masatsugu Hori; David H. MacLennan
• Keywords: Phospholamban; Contractility; SERCA; Calsequestrin

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in heart might impair function, transgenic (TG) mice were generated with cardiac-specific NF-SLN (SLN tagged at its N terminus FLAG epitope). The level expression (the NF-SLN/PLN ratio) was equivalent to that which induces profound superinhibition when coexpressed PLN SERCA2a HEK-293 cells. In TG hearts, apparent affinity for decreased compared non-TG littermate control hearts. Invasive hemodynamic echocardiographic analyses revealed impaired contractility ventricular hypertrophy mice. Basal phosphorylation reduced. isolated papillary muscle subjected isometric tension, peak amplitudes transients tensions reduced, whereas decay times relaxation tension increased Isoproterenol largely restored stimulated wild-type levels intact No compensatory changes SERCA2a, PLN, ryanodine receptor, calsequestrin observed Coimmunoprecipitation indicated overexpressed bound both forming a ternary complex. These data suggest stabilization SERCA2a-PLN interaction absence inhibition phosphorylation. Inhibition impairs calcium cycling, but responsiveness beta-adrenergic agonists may prevent progression failure.