Cyclosporin A Inhibits Inositol 1,4,5-Trisphosphate-dependent Ca2+ Signals by Enhancing Ca2+ Uptake into the Endoplasmic Reticulum and Mitochondria

• Published in: The Journal of biological chemistry 2001-06, Vol.276 (26), p.23329-23340
• Main Authors: Smaili, Soraya S., Stellato, Kerri Anne, Burnett, Paul, Thomas, Andrew P., Gaspers, Lawrence D.
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Signaling; Cell Membrane - metabolism; Cells, Cultured; Cyclosporine - pharmacology; Endoplasmic Reticulum - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Immunosuppressive Agents - pharmacology; Inositol 1,4,5-Trisphosphate - antagonists & inhibitors; Intracellular Membranes - metabolism; Ion Transport - drug effects; Kinetics; Male; Membrane Potentials; Mitochondria - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100989200

Cytosolic Ca2+([Ca2+]i) oscillations may be generated by the inositol 1,4,5-trisphosphate receptor (IP3R) driven through cycles of activation/inactivation by local Ca2+feedback. Consequently, modulation of the local Ca2+gradients influences IP3R excitability as well as the duration and amplitude of the [Ca2+]ioscillations. In the present work, we demonstrate that the immunosuppressant cyclosporin A (CSA) reduces the frequency of IP3-dependent [Ca2+]ioscillations in intact hepatocytes, apparently by altering the local Ca2+ gradients. Permeabilized cell experiments demonstrated that CSA lowers the apparent IP3 sensitivity for Ca2+ release from intracellular stores. These effects on IP3-dependent [Ca2+]isignals could not be attributed to changes in calcineurin activity, altered ryanodine receptor function, or impaired Ca2+fluxes across the plasma membrane. However, CSA enhanced the removal of cytosolic Ca2+ by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), lowering basal and inter-spike [Ca2+]i. In addition, CSA stimulated a stable rise in the mitochondrial membrane potential (ΔΨm), presumably by inhibiting the mitochondrial permeability transition pore, and this was associated with increased Ca2+ uptake and retention by the mitochondria during a rise in [Ca2+]i. We suggest that CSA suppresses local Ca2+ feedback by enhancing mitochondrial and endoplasmic reticulum Ca2+ uptake, these actions of CSA underlie the lower IP3 sensitivity found in permeabilized cells and the impaired IP3-dependent [Ca2+]i signals in intact cells. Thus, CSA binding proteins (cyclophilins) appear to fine tune agonist-induced [Ca2+]i signals, which, in turn, may adjust the output of downstream Ca2+-sensitive pathways.