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Inhibition of store-operated calcium entry attenuates MPP(+)-induced oxidative stress via preservation of mitochondrial function in PC12 cells: involvement of Homer1a.

ABSTRACT: The process of store-operated calcium entry (SOCE), whereby the release of intracellular Ca(2+) from endoplasmic reticulum (ER) activates Ca(2+) influx channels in the plasma membrane, has been demonstrated to impact a diverse range of cell functions. In the present study, we investigated the potential protective effect of SOCE inhibition against 1-methyl-4-phenylpyridinium (MPP(+)) injury by using pharmacological antagonists or specific small interfering RNA (siRNA) in PC12 cells. The results showed that both antagonists (15 ?M MRS-1845 and 50 ?M ML-9) and stromal interacting molecule-1 (STIM1) targeted siRNA (Si-STIM1) significantly increased cell viability, decreased apoptotic cell death and reduced intracellular reactive oxygen species (ROS) production and lipid peroxidation in MPP(+) injured PC12 cells. SOCE inhibition also prevented MPP(+) induced mitochondrial dysfunction and activation of mitochondrial related apoptotic factors, while had no effect on mitochondrial biogenesis. Moreover, inhibition of SOCE by antagonists and siRNA increased the expression levels of Homer1a mRNA and protein, and knockdown of Homer1a expression by specific siRNA partly reversed the protective effects induced by SOCE inhibition in PC12 cells. All these results indicated that SOCE inhibition protected PC12 cells against MPP(+) insult through upregulation of Homer1a expression, and SOCE might be an ideal target for investigating therapeutic strategy against neuronal injury in PD patients.

SUBMITTER: Li X

PROVIDER: S-EPMC3866123 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Inhibition of store-operated calcium entry attenuates MPP(+)-induced oxidative stress via preservation of mitochondrial function in PC12 cells: involvement of Homer1a.

Li Xia X Chen Wei W Zhang Lei L Liu Wen-bo WB Fei Zhou Z

PloS one 20131217 12

The process of store-operated calcium entry (SOCE), whereby the release of intracellular Ca(2+) from endoplasmic reticulum (ER) activates Ca(2+) influx channels in the plasma membrane, has been demonstrated to impact a diverse range of cell functions. In the present study, we investigated the potential protective effect of SOCE inhibition against 1-methyl-4-phenylpyridinium (MPP(+)) injury by using pharmacological antagonists or specific small interfering RNA (siRNA) in PC12 cells. The results s ...[more]

PMID: 24358303

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Project description:Redox modulation participates in the regulation of intracellular free calcium concentration ([Ca(2+)](i)) in several cell types. In thyroid cells, including FRTL-5 cells, changes in [Ca(2+)](i) regulate several important functions, including the production of H(2)O(2) (hydrogen peroxide). As H(2)O(2) is of crucial importance for the production of thyroid hormones, we investigated the effects of H(2)O(2) on [Ca(2+)](i) in thyroid FRTL-5 cells. H(2)O(2) itself did not modulate basal [Ca(2+)](i). However, H(2)O(2) attenuated store-operated calcium entry evoked by thapsigargin, both in a sodium-containing buffer and in a sodium-free buffer. The effect of H(2)O(2) was abrogated by the reducing agent beta-mercaptoethanol. H(2)O(2) also attenuated the thapsigargin-evoked entry of barium and manganese. The effect of H(2)O(2) was, at least in part, mediated by activation of protein kinase C (PKC), as H(2)O(2) enhanced the binding of [(3)H]phorbol 12,13-dibutyrate. H(2)O(2) also stimulated the translocation of the isoenzyme PKCepsilon from the cytosolic fraction to the particulate fraction. Furthermore, H(2)O(2) did not attenuate store-operated calcium entry in cells treated with staurosporine or calphostin C, or in cells with down-regulated PKC. H(2)O(2) depolarized the membrane potential in bisoxonol-loaded cells and when patch-clamp in the whole-cell mode was used. The depolarization was attenuated in cells with down-regulated PKC. This depolarization, at least in part, explained the H(2)O(2)-evoked inhibition of calcium entry. In addition, H(2)O(2) enhanced the extrusion of calcium from cells stimulated with thapsigargin and this effect was abolished in cells with down-regulated PKC and after treatment of the cells with the reducing agent beta-mercaptoethanol. In conclusion H(2)O(2) attenuates an increase in [Ca(2+)](i). As H(2)O(2) is produced in thyroid cells in a calcium-dependent manner, our results suggest that H(2)O(2) may participate in the regulation of [Ca(2+)](i) in these cells via a negative-feedback mechanism involving activation of PKC.

Dataset Information

Inhibition of store-operated calcium entry attenuates MPP(+)-induced oxidative stress via preservation of mitochondrial function in PC12 cells: involvement of Homer1a.

Publications

Inhibition of store-operated calcium entry attenuates MPP(+)-induced oxidative stress via preservation of mitochondrial function in PC12 cells: involvement of Homer1a.

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