Cyclosporin A inhibits inositol 1,4,5-trisphosphate-dependent Ca2+ signalsby enhancing Ca2+ uptake into the endoplasmic reticulum and mitochondria

Cytosolic Ca2+ ([Ca2+](i)) oscillations may be generated by the inositol 1, 4,5-trisphosphate receptor (IP3R) driven through cycles of activation/inact ivation by local Ca2+. feedback. Consequently, modulation of the local Ca2 gradients influences IP3R excitability as well as the duration and amplitu de of the [Ca2+](i) oscillations. In the present work, we demonstrate that the immunosuppressant cyclosporin A (CSA) reduces the frequency of IP3-depe ndent [Ca2+](i) oscillations in intact hepatocytes, apparently by altering the local Ca2+ gradients. Permeabilized cell experiments demonstrated that CSA lowers the apparent IF, sensitivity for Ca2+ release from intracellular stores. These effects on IP3-dependent [Ca2+](i) signals could not be attr ibuted to changes in calcineurin activity, altered ryanodine receptor funct ion, or impaired Ca2+ fluxes across the plasma membrane. However, CSA enhan ced the removal of cytosolic Ca2+ by sarco-endoplasmic reticulum Ca2+-ATPas e (SERCA), lowering basal and interspike [Ca2+](i). In addition, CSA stimul ated a stable rise in the mitochondrial membrane potential (Delta psi (m)), presumably by inhibiting the mitochondrial permeability transition pore, a nd this was associated with increased Ca2+ uptake and retention by the mito chondria during a rise in [Ca2+](i). We suggest that CSA suppresses local C a2+ feedback by enhancing mitochondrial and endoplasmic reticulum Ca2+ upta ke, these actions of CSA underlie the lower IP3 sensitivity found in permea bilized cells and the impaired IP3-dependent [Ca2+](i) signals in intact ce lls. Thus, CSA binding proteins (cyclophilins) appear to fine tune agonist- induced [Ca2+](i) signals, which, in turn, may adjust the output of downstr eam Ca2+-sensitive pathways.