| The ryanodine receptor (RyR) controls calcium release from the intracellular calcium store in striated muscle, the sarcoplasmic reticulum (SR). Gating of RyR2, the predominant isoform in cardiac myocytes, is modulated by components of the RyR2 macromolecular complex, one of which is calstabin2 (FKBP12.6). Calstabin2, a 12.6 kDa cis-trans peptidyl-prolyl isomerase, has an important cellular physiological function with regard to intracellular calcium release, but the underlying molecular mechanisms have not been fully explained. Protein kinase A (PKA) phosphorylation of RyR2 decreases the binding affinity of calstabin2 to the RyR2 channel complex. Using mutagenesis of calstabin2, we identified residues that mediate the binding of calstabin2 to PKA-phosphorylated RyR2. Our findings provide a structural basis for the reduced binding affinity of calstabin2 to PKA-phosphorylated RyR2.; Increasing evidence shows that disruption of calcium homeostasis in cardiac myocytes leads to cardiac arrhythmias and heart failure. We assessed the utility of the caltabin2-RyR2 interaction as a therapeutic target in a mouse model of heart failure. Our studies show that retention of the calstabin2-RyR2 interaction upon PKA hyperphosphorylation in heart failure results in improved cardiac function and decreased severity of disease. Thus, therapeutic strategies focused on this interaction can lead to promising novel treatments for heart disease. |
