Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients

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 n...

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Main Authors: Lisann Pelzl, Bhaeldin Elsir, Itishri Sahu, Rosi Bissinger, Yogesh Singh, Basma Sukkar, Sabina Honisch, Ludger Schoels, Mohamed Jemaà, Elisabeth Lang, Alexander Storch, Andreas Hermann, Christos Stournaras, Florian Lang
Format: Article
Language:English
Published: Cell Physiol Biochem Press GmbH & Co KG 2017-08-01
Series:Cellular Physiology and Biochemistry
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Online Access:http://www.karger.com/Article/FullText/479901
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spelling doaj-c16cff9c9b354f11b36020e51e56bb642020-11-25T00:40:29ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782017-08-014252066207710.1159/000479901479901Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis PatientsLisann PelzlBhaeldin ElsirItishri SahuRosi BissingerYogesh SinghBasma SukkarSabina HonischLudger SchoelsMohamed JemaàElisabeth LangAlexander StorchAndreas HermannChristos StournarasFlorian LangBackground: 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. 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. 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. 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.http://www.karger.com/Article/FullText/479901CalciumSOCELithiumApoptosisNeurodegenerationOrai1Cell membrane scrambling
collection DOAJ
language English
format Article
sources DOAJ
author Lisann Pelzl
Bhaeldin Elsir
Itishri Sahu
Rosi Bissinger
Yogesh Singh
Basma Sukkar
Sabina Honisch
Ludger Schoels
Mohamed Jemaà
Elisabeth Lang
Alexander Storch
Andreas Hermann
Christos Stournaras
Florian Lang
spellingShingle Lisann Pelzl
Bhaeldin Elsir
Itishri Sahu
Rosi Bissinger
Yogesh Singh
Basma Sukkar
Sabina Honisch
Ludger Schoels
Mohamed Jemaà
Elisabeth Lang
Alexander Storch
Andreas Hermann
Christos Stournaras
Florian Lang
Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
Cellular Physiology and Biochemistry
Calcium
SOCE
Lithium
Apoptosis
Neurodegeneration
Orai1
Cell membrane scrambling
author_facet Lisann Pelzl
Bhaeldin Elsir
Itishri Sahu
Rosi Bissinger
Yogesh Singh
Basma Sukkar
Sabina Honisch
Ludger Schoels
Mohamed Jemaà
Elisabeth Lang
Alexander Storch
Andreas Hermann
Christos Stournaras
Florian Lang
author_sort Lisann Pelzl
title Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
title_short Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
title_full Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
title_fullStr Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
title_full_unstemmed Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
title_sort lithium sensitivity of store operated ca2+ entry and survival of fibroblasts isolated from chorea-acanthocytosis patients
publisher Cell Physiol Biochem Press GmbH & Co KG
series Cellular Physiology and Biochemistry
issn 1015-8987
1421-9778
publishDate 2017-08-01
description 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. 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. 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. 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.
topic Calcium
SOCE
Lithium
Apoptosis
Neurodegeneration
Orai1
Cell membrane scrambling
url http://www.karger.com/Article/FullText/479901
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