CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

Aging Cell

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 】

Summary

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.

【 授权许可】

CC BY   
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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