Ryanodine receptor in heart failure: potential therapeutic sites.

• Main Author: Guy Vasort (Author)
• Format: Book
• Published: ECIMED, 2010-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Heart failure (HF) is one of the most important contributors to morbidity and mortality from cardiac diseases. Ca2+ handling abnormalities play an important role in the development of HF. The ryanodine receptor, RyR2 is a large tetrameric protein associated with FK506-binding immunophilin protein, FKBP12.6 or calstabin2 and many kinases and phosphatases to form a huge complex. FKBP12.6 is thought to maintain the RyR2 in a closed state. Hyperphosphorylated state of RyR2 and FKBP12.6 dissociation occur in heart failure. RyR2 leakage may not necessarily depend upon phosphorylation. Other mechanisms include unzipping of the N-terminal and central domains of RyR2, and abnormal sensing of the sarcoplasmic reticulum (SR) Ca2+ load. The 1,4-benzothiazepine derivative JTV519/K201 has significant beneficial contractile effect in HF. Several models are proposed to account for its restoring effects. Heart failure is also accompanied by increased oxidative stress and NOsynthase activity that both alter RyR2 properties and lead to RyR2 leak. SR-Ca2+ release can be antagonized by reducing agents and by S107, a K201-analog. Abnormal SR-Ca2+ release during diastole also results in changes in membrane potential and the triggering of ventricular arrhythmia. Besides the above alterations in RyR2 properties, multiple mutations occurring in RyR2 protein are linked to catecholaminergic polymorphic ventricular tachycardia. The anti-arrhythmic properties of K201 and its mechanisms of action remain controversial. Controlling the interactions RyR2 - FKBP12.6 could be an important candidate target for pharmaceutical management of cardiac insufficiency and ventricular arrhythmia during HF.

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