STABILIZATION OF CALCIUM-RELEASE CHANNEL (RYANODINE RECEPTOR) FUNCTION BY FK506-BINDING PROTEIN

FK506-binding protein (FKBP12) was originally identified as the cytoso lic receptor for the immunosuppressant drugs FK506 and rapamycin. The cellular function of FKBP12, a ubiquitously expressed 12,000-dalton pr oline isomerase, has been unknown. FKBP12 copurifies with the 565,000- dalton ryanodine receptor (RyR), four of which form intracellular Ca2 release channels of the sarcoplasmic and endoplasmic reticula. By coe xpressing the RyR and FKBP12 in insect cells, we have demonstrated tha t FKBP12 modulates channel gating by increasing channels with full con ductance levels (by >400%), decreasing open probability after caffeine activation (from 0.63 +/- 0.09 to 0.04 +/- 0.02), and increasing mean open time (from 4.4 +/- 0.6 ms to 75 +/- 41 ms). FK506 or rapamycin, inhibitors of FKBP12 isomerase activity, reverse these stabilizing eff ects. These results provide the first natural cellular function for FK BP12, and establish that the functional Ca2+ release channel complex i ncludes FKBP12.