Rectification of skeletal muscle ryanodine receptor mediated by FK506 binding protein.
The cytosolic receptor for immunosuppressant drugs, FK506 binding protein (FKBP12), maintains a tight association with ryanodine receptors of sarcoplasmic reticulum (SR) membrane in skeletal muscle. The interaction between FKBP12 and ryanodine receptors resulted in distinct rectification of the Ca release channel. The endogenous FKBP-bound Ca release channel conducted current unidirectionally from SR lumen to myoplasm; in the opposite direction, the channel deactivated with fast kinetics. The binding of FKBP12 is likely to alter subunit interactions within the ryanodine receptor complex, as revealed by changes in conductance states of the channel. Both on- and off-rates of FKBP12 binding to the ryanodine receptor showed clear dependence on the membrane potential, suggesting that the binding sites of FKBP12 reside in or near the conduction pore of the Ca release channel. Rectification of the Ca release channel would prevent counter-current flow during the rapid release of Ca from SR membrane, and thus may serve as a negative feedback mechanism that participates in the process of muscle excitation-contraction coupling.
Ma
J
J
Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA. jxm63@po.cwru.edu
Bhat
M B
MB
Zhao
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004553:Electric Conductivity; D004594:Electrophysiology / Q000295:instrumentation / Q000379:methods; D006360:Heat-Shock Proteins / Q000502:physiology*; D015640:Ion Channel Gating; D007700:Kinetics; D008051:Lipid Bilayers; D008564:Membrane Potentials; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D011485:Protein Binding; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D013997:Time Factors
D015220:Calcium Channels; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D008051:Lipid Bilayers; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D016559:Tacrolimus