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Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients.
- Source :
-
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology [Cell Physiol Biochem] 2017; Vol. 42 (5), pp. 2066-2077. Date of Electronic Publication: 2017 Aug 11. - Publication Year :
- 2017
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Abstract
- Background: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment.<br />Methods: Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry.<br />Results: SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 µM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB.<br />Conclusions: In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment.<br /> (© 2017 The Author(s). Published by S. Karger AG, Basel.)
- Subjects :
- Apoptosis drug effects
Boron Compounds pharmacology
Calcium metabolism
Calcium Release Activated Calcium Channels antagonists & inhibitors
Calcium-Transporting ATPases metabolism
Case-Control Studies
Cell Survival drug effects
Cells, Cultured
Down-Regulation drug effects
Fibroblasts cytology
Fibroblasts metabolism
Fura-2 chemistry
Heterocyclic Compounds, 3-Ring pharmacology
Humans
Microscopy, Fluorescence
Neuroacanthocytosis metabolism
Calcium Release Activated Calcium Channels metabolism
Fibroblasts drug effects
Lithium pharmacology
Neuroacanthocytosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1421-9778
- Volume :
- 42
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 28803243
- Full Text :
- https://doi.org/10.1159/000479901