Overexpression of FKBP12.6 to influence SR function

Contractile capacity of the heart is critically dependent on sarcoplasmic reticulum (SR) function. Ca2+-handling proteins of the SR may therefore represent promising molecular targets for genetic approaches to improve cardiac function. The ryanodine receptor (RyR) is the primary intracellular Ca2+-release channel in striated muscles mediating muscle contraction by regulating the release of Ca2+ from the SR. The skeletal muscle RyR isoform (RyR1) is tightly associated with the FK506-binding protein 12 (FKBP12), whereas the cardiac RyR (RyR2) is known to bind the homologous isoform FKBP12.6. Recent studies indicate that FKBP12 modulates channel function by increasing conductivity and by stabilizing its closed conformation state. However, the precise role of FKBP12.6 in cardiac excitation-contraction coupling (E-C coupling) is not clear.