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

• Autor(a) principal: Smaili, Soraya Soubhi [UNIFESP]
• Data de Publicação: 2001
• Outros Autores: Stellato, K. A., Burnett, P., Thomas, A. P., Gaspers, L. D.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.1074/jbc.M100989200; http://repositorio.unifesp.br/handle/11600/26583

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+](i) oscillations. in the present work, we demonstrate that the immunosuppressant cyclosporin A (CSA) reduces the frequency of IP3-dependent [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 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 interspike [Ca2+](i). in addition, CSA stimulated a stable rise in the mitochondrial membrane potential (Delta psi (m)), 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.