Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8473935 | Journal of Molecular and Cellular Cardiology | 2016 | 34 Pages |
Abstract
One approach to improve contraction in the failing heart is the administration of calcium (Ca2Â +) sensitizers. Although it is known that levosimendan and other sensitizers bind to troponin C (cTnC), their in vivo mechanism is not fully understood. Based on levosimendan, we designed a covalent Ca2Â + sensitizer (i9) that targets C84 of cTnC and exchanged this complex into cardiac muscle. The NMR structure of the covalent complex showed that i9 binds deep in the hydrophobic pocket of cTnC. Despite slightly reducing troponin I affinity, i9 enhanced the Ca2Â + sensitivity of cardiac muscle. We conclude that i9 enhances Ca2Â + sensitivity by stabilizing the open conformation of cTnC. These findings provide new insights into the in vivo mechanism of Ca2Â + sensitization and demonstrate that directly targeting cTnC has significant potential in cardiovascular therapy.
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Authors
Sandra E. Pineda-Sanabria, Ian M. Robertson, Yin-Biao Sun, Malcolm Irving, Brian D. Sykes,