Ryanodine receptor-FK506-binding protein complex (RyR-FKBP complex)

The Ryanodine receptor-FK506-binding protein complex is a critical macromolecular assembly that regulates intracellular calcium (Ca2+) release in striated muscles (Gonano & Jones, 2017, PMID: 28636428). This complex consists of the homotetrameric ryanodine receptor (RyR1 in skeletal muscle or RyR2 in cardiac muscle) and its stabilizing subunits, the FK506-binding proteins FKBP12 (calstabin1) and FKBP12.6 (calstabin2) (Marks, 2013, PMID: 23345450). Under normal physiological conditions, the binding of FKBPs to the RyR tetramer stabilizes the channel in its closed state, ensuring that Ca2+ is only released during active contraction and preventing pathological leak during the resting phase (diastole) (Lacampagne et al., 2017, PMID: 28823915). In diseases such as heart failure, cardiac arrhythmias, and skeletal myopathies, the RyR-FKBP interaction is disrupted by factors like hyperphosphorylation or oxidative stress, leading to chronic Ca2+ leak that impairs muscle function and triggers arrhythmias (Andersson et al., 2011, PMID: 21723186). Therapeutic agents known as Rycals (e.g., S107, ARM210) are designed to stabilize these complexes and restore normal Ca2+ handling by increasing the affinity of FKBPs for the RyR (Dridi et al., 2020, PMID: 32315316). Conversely, immunosuppressants like FK506 (tacrolimus) and rapamycin (sirolimus) can disrupt these complexes, which is a known mechanism for some of their adverse effects on muscle and heart function (Gonano & Jones, 2017, PMID: 28636428).

Other names

Ryanodine receptor-calstabin complexCalstabin-ryanodine receptor complexRyR-FKBP complexRyR1-FKBP12 complexRyR2-FKBP12.6 complexRyanodine receptor-associated FKBP12/12.6 complex

Rycals (e.g., S107, ARM210) act as stabilizers of the RyR-FKBP complex by increasing the binding affinity of FKBP12 or FKBP12.6 to the ryanodine receptor, thereby preventing the pathological diastolic calcium leak associated with heart failure and arrhythmias (Marks, 2013, PMID: 23345450).