Different interactions of cardiac and skeletal muscle ryanodine receptors with FK-506 binding protein isoforms

In the present study, we compare functional consequences of dissociation and reconstitution of binding proteins FKBP12 and FKBP12.6 with ryanodine receptors from cardiac (RyR(2)) and skeletal muscle (RyR(1)). The skeletal muscle RyR(1) channel became activated on removal of endogenously bound FKBP12, consistent with previous reports. Both FKBP12 and FKBP12.6 rebind to FKBP-depleted RyR(1) and restore its quiescent channel behavior by altering Ligand sensitivity, as studied by single-channel recordings in planar lipid bilayers, and macroscopic behavior of the channels (ryanodine binding and net energized Ca2+ uptake). By contrast, removal of FKBP12.6 from the cardiac RyR(2) did not modulate the function of the channel using the same types of assays as for RyR(1). FKBP12 or FKBP12.6 had no effect on channel activity of FKBP12.6-depleted cardiac RyR(2), although FKBP12.6 rebinds. Our studies reveal important differences between the two ryanodine receptor isoforms with respect to their functional interaction with FKBP12 and FKBP12.6.