Intracellular calcium release channels on the endoplasmic or sarcoplasmic reticula (ryanodine receptors, RyR, and inositol 1,4,5-trisphosphate receptors, IP(3)R) comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in many cellular signaling pathways including excitation-contraction coupling, oocyte fertilization, hormone secretion, neurotransmitter release, and T lymphocyte activation. Three forms of RyR have been identified: RyR1 expressed predominantly in skeletal muscle, RyR2 in cardiac muscle, and RyR3 in the brain. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein, FKBP12. The immunosuppressant drugs FK506 and rapamycin inhibit the prolyl isomerase activity of FKBP12 and could cause cardiac dysfunction by inducing a Ca(2+) leak from the sarcoplasmic reticulum. RyR2 is downregulated and IP(3)R is upregulated during severe end-stage heart failure secondary to dilated cardiomyopathies in humans, suggesting that these channels may contribute to abnormalities in Ca(2+) homeostasis.

FK506-binding protein (FKBP12) was originally identified as the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin. The cellular function of FKBP12, a ubiquitously expressed 12,000-dalton proline 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 coexpressing the RyR and FKBP12 in insect cells, we have demonstrated that FKBP12 modulates channel gating by increasing channels with full conductance 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 effects. These results provide the first natural cellular function for FKBP12, and establish that the functional Ca2+ release channel complex includes FKBP12.