Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

Honisch, Sabina; Fehrenbacher, Birgit; Lebedeva, Aleksandra; Alesutan, Ioana; Castor, Tatsiana; Alkahtani, Saad; Alarifi, Saud; Schaller, Martin; Stournaras, Christos; Läng, Florian

doi:10.1159/000442599

Cited by 17 publications

(16 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In platelets, chorein deficiency decreases the number of intracellular granules and compromises platelet degranulation [15]. Chorein deficiency further compromizes dopamine release in pheochromocytoma (PC12) cells [16, 17]. In fibroblasts isolated from ChAc-patients cytoskeletal architecture is severely distorted [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Pelzl

Elsir

Sahu

et al. 2017

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Chorein deficiency further compromizes dopamine release in pheochromocytoma (PC12) cells [16, 17]. In fibroblasts isolated from ChAc-patients cytoskeletal architecture is severely distorted [17]. …”

Section: Introductionmentioning

confidence: 99%

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

Pelzl

Elsir

Sahu

et al. 2017

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

show abstract

“…In PC12 cells, chorein silencing compromises the expression of vesicle-associated membrane protein 8 (VAMP8) and reduces the number of vesicles [36]. As a result, chorein silencing blunts the stimulation of dopamine release following depolarization of the cell membrane by increase of extracellular K+ [36, 42].…”

Section: Exocytosis Transmitter Release and Platelet Degranulationmentioning

confidence: 99%

“…As a result, chorein silencing blunts the stimulation of dopamine release following depolarization of the cell membrane by increase of extracellular K+ [36, 42]. …”

Section: Exocytosis Transmitter Release and Platelet Degranulationmentioning

confidence: 99%

See 1 more Smart Citation

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

Self Cite

View full text Add to dashboard Cite

Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca²⁺-channel accomplishing store operated Ca²⁺-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.

show abstract