Aging Cell | |
CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β | |
Ana José Moreno-Ortega2  Izaskun Buendia3  Lamia Mouhid1  Javier Egea2  Susana Lucea3  Ana Ruiz-Nuño2  Manuela G. López2  | |
[1] Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain;Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain | |
关键词: Alzheimer's disease; Ca2+ channel CALHM1; CREB; Ca2+ homeostasis; caspases; early apoptosis; | |
DOI : 10.1111/acel.12403 | |
来源: Wiley | |
【 摘 要 】
The mutated form of the Ca2+ channel CALHM1 (Ca2+ homeostasis modulator 1), P86L-CALHM1, has been correlated with early onset of Alzheimer's disease (AD). P86L-CALHM1 increases production of amyloid beta (Aβ) upon extracellular Ca2+ removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L-CALHM, upon Aβ treatment, on the following: (i) the intracellular Ca2+ signal pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Aβ. Using aequorins to measure the effect of nuclear Ca2+ concentrations ([Ca2+]n) and cytosolic Ca2+ concentrations ([Ca2+]c) on Ca2+ entry conditions, we observed that baseline [Ca2+]n was higher in CALHM1 and P86L-CALHM1 cells than in control cells. Moreover, exposure to Aβ affected [Ca2+]c levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1 compared with control cells. Treatment with Aβ elicited a significant decrease in the cell survival proteins p-ERK and p-CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L-CALHM1-overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Aβ, P86L-CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro-cytotoxic pathways, thus potentially contributing to its deleterious effects in AD.Summary
【 授权许可】
CC BY
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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