Peptidyl-prolyl cis-trans isomerase FKBP1B–Ryanodine receptor 2 complex (FKBP12.6–RyR2 complex) (FKBP12.6–RyR2 complex)

The Peptidyl-prolyl cis-trans isomerase FKBP1B–Ryanodine receptor 2 complex (FKBP12.6–RyR2 complex) is a critical regulatory assembly in cardiac myocytes that governs calcium-induced calcium release (CICR) from the sarcoplasmic reticulum (UniProt Q92736). RyR2 serves as the pore-forming subunit of the calcium release channel, while FKBP12.6 (also known as Calstabin2) acts as a stabilizing accessory protein that binds to RyR2 to maintain the channel in a closed state during the resting phase (diastole) of the cardiac cycle (Marks, 2003). Dissociation of FKBP12.6 from RyR2, often triggered by hyperphosphorylation of RyR2 by protein kinase A (PKA) or CaMKII, results in diastolic calcium leaks that contribute to the pathogenesis of heart failure and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Wehrens et al., 2004). These leaks can induce delayed afterdepolarizations (DADs), leading to fatal arrhythmias and reduced cardiac contractility. Therapeutic interventions focus on Rycals, a class of small molecules like S107 and ARM210, which are designed to stabilize the complex by enhancing the affinity of FKBP12.6 for RyR2, thereby preventing pathological calcium leakage (Andersson & Marks, 2010). This complex represents a major target for treating cardiovascular diseases characterized by calcium handling dysfunction.

Other names

FKBP1B–RyR2 complexCalstabin2–RyR2 complexFK506-binding protein 12.6–Ryanodine receptor 2 complexFKBP12.6–RyR2 complex

Stabilization of the RyR2 channel closed state by restoring or enhancing the binding of FKBP12.6 to the RyR2 tetramer, thereby preventing diastolic calcium leakage (Wehrens et al., 2004).