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

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

Autor Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Stellato, K. A. Google Scholar
Burnett, P. Google Scholar
Thomas, A. P. Google Scholar
Gaspers, L. D. Google Scholar
Instituição New Jersey Med Sch
Universidade Federal de São Paulo (UNIFESP)
Resumo 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.
Idioma Inglês
Data de publicação 2001-06-29
Publicado em Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 276, n. 26, p. 23329-23340, 2001.
ISSN 0021-9258 (Sherpa/Romeo, fator de impacto)
Publicador Amer Soc Biochemistry Molecular Biology Inc
Extensão 23329-23340
Fonte http://dx.doi.org/10.1074/jbc.M100989200
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000169531100017
Endereço permanente http://repositorio.unifesp.br/handle/11600/26583

Exibir registro completo




Arquivo

Arquivo Tamanho Formato Visualização

Não existem arquivos associados a este item.

Este item está nas seguintes coleções

Buscar


Navegar

Minha conta