Cyclosporin A Inhibits Inositol 1,4,5-Trisphosphate-dependent Ca super(2+) Signals by Enhancing Ca super(2+) 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, S S, Stellato, KA, Burnett, P, Thomas, AP, Gaspers, L D
• Format: Article
• Language: English
• ISSN: 0021-9258

Cytosolic Ca super(2+) ([Ca super(2+)] sub(i)) oscillations may be generated by the inositol 1,4,5-trisphosphate receptor (IP sub(3)R) driven through cycles of activation/inactivation by local Ca super(2+) feedback. Consequently, modulation of the local Ca super(2+) gradients influences IP sub(3)R excitability as well as the duration and amplitude of the [Ca super(2+)] sub(i) oscillations. In the present work, we demonstrate that the immunosuppressant cyclosporin A (CSA) reduces the frequency of IP sub(3)-dependent [Ca super(2+)] sub(i) oscillations in intact hepatocytes, apparently by altering the local Ca super(2+) gradients. Permeabilized cell experiments demonstrated that CSA lowers the apparent IP sub(3) sensitivity for Ca super(2+) release from intracellular stores. These effects on IP sub(3)-dependent [Ca super(2+)] sub(i) signals could not be attributed to changes in calcineurin activity, altered ryanodine receptor function, or impaired Ca super(2+) fluxes across the plasma membrane. However, CSA enhanced the removal of cytosolic Ca super(2+) by sarco-endoplasmic reticulum Ca super(2+)-ATPase (SERCA), lowering basal and inter-spike [Ca super(2+)] sub(i). In addition, CSA stimulated a stable rise in the mitochondrial membrane potential ( Delta psi sub(m)), presumably by inhibiting the mitochondrial permeability transition pore, and this was associated with increased Ca super(2+) uptake and retention by the mitochondria during a rise in [Ca super(2+)] sub(i). We suggest that CSA suppresses local Ca super(2+) feedback by enhancing mitochondrial and endoplasmic reticulum Ca super(2+) uptake, these actions of CSA underlie the lower IP sub(3) sensitivity found in permeabilized cells and the impaired IP sub(3)-dependent [Ca super(2+)] sub(i) signals in intact cells. Thus, CSA binding proteins (cyclophilins) appear to fine tune agonist-induced [Ca super(2+)] sub(i) signals, which, in turn, may adjust the output of downstream Ca super(2+)-sensitive pathways.