Abstract
Cytosolic Ca(2+) ([Ca(2+)](i)) oscillations may be generated by the inositol 1,4,5-trisphosphate receptor (IP(3)R) driven through cycles of activation/inactivation by local Ca(2+) feedback. Consequently, modulation of the local Ca(2+) gradients influences IP(3)R excitability as well as the duration and amplitude of the [Ca(2+)](i) oscillations. In the present work, we demonstrate that the immunosuppressant cyclosporin A (CSA) reduces the frequency of IP(3)-dependent [Ca(2+)](i) oscillations in intact hepatocytes, apparently by altering the local Ca(2+) gradients. Permeabilized cell experiments demonstrated that CSA lowers the apparent IP(3) sensitivity for Ca(2+) release from intracellular stores. These effects on IP(3)-dependent [Ca(2+)](i) signals could not be attributed to changes in calcineurin activity, altered ryanodine receptor function, or impaired Ca(2+) fluxes across the plasma membrane. However, CSA enhanced the removal of cytosolic Ca(2+) by sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), lowering basal and inter-spike [Ca(2+)](i). In addition, CSA stimulated a stable rise in the mitochondrial membrane potential (DeltaPsi(m)), presumably by inhibiting the mitochondrial permeability transition pore, and this was associated with increased Ca(2+) uptake and retention by the mitochondria during a rise in [Ca(2+)](i). We suggest that CSA suppresses local Ca(2+) feedback by enhancing mitochondrial and endoplasmic reticulum Ca(2+) uptake, these actions of CSA underlie the lower IP(3) sensitivity found in permeabilized cells and the impaired IP(3)-dependent [Ca(2+)](i) signals in intact cells. Thus, CSA binding proteins (cyclophilins) appear to fine tune agonist-induced [Ca(2+)](i) signals, which, in turn, may adjust the output of downstream Ca(2+)-sensitive pathways.
Highlights
Immunosuppressants exert their activity by binding to immunophilins, an evolutionary conserved, but structurally heterogeneous family of proteins that shares a common enzymatic activity and pharmacological profile [1,2,3]
Immunophilins are divided into two classes: (a) the cyclophilin family that selectively binds cyclosporin A (CSA)1 and (b) the FK-506 binding proteins (FKBP), which bind to FK-506, its analogues, and rapamycin
CSA binds to cyclophilin D (CyPD), which is believed to be a component of the mitochondrial permeability transition pore (PTP)
Summary
Permeabilized cell experiments demonstrated that CSA lowers the apparent IP3 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. 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. Immunosuppressants exert their activity by binding to immunophilins, an evolutionary conserved, but structurally heterogeneous family of proteins that shares a common enzymatic activity and pharmacological profile [1,2,3]. Cyclophilins may play an essential role in determining the shape and frequency of IP3-dependent [Ca2ϩ]i signals and, the activity of downstream Ca2ϩ-sensitive targets by regulating cellular Ca2ϩ transport mechanisms
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