RYANODINE RECEPTORS FROM RABBIT SKELETAL-MUSCLE ARE REVERSIBLY ACTIVATED BY RAPAMYCIN

In this report we demonstrate that the immunosuppressive drug, rapamyc in, can reversibly activate the skeletal muscle ryanodine receptor cal cium release channel (RyR) in terminal cisternae vesicles incorporated into planar lipid bilayers. This reveals a second mechanism of activa tion of RyRs by rapamycin. Irreversible channel activation and opening s to subconductance levels are seen when rapamycin forms a complex wit h and removes the tightly bound 12 kDa FK506-binding protein (FKBP12) from the RyR. We show here that micromolar rapamycin activates RyRs wh ich were previously 'stripped' of >95% of their FKBP12s. Rapamycin cau sed a 6-fold increase in mean current, which was largely reversible, b ut no increase in the fraction of openings to subconductance levels. T herefore native RyRs, stripped of FKBP12, are directly activated by th e macrocyclic lactone, rapamycin. (C) 1997 Elsevier Science Ireland Lt d.