Open AccessCALHM 1 and its polymorphism P86L differentially control Ca 2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β
Author(s) -
MorenoOrtega Ana José,
Buendia Izaskun,
Mouhid Lamia,
Egea Javier,
Lucea Susana,
RuizNuño Ana,
López Manuela G.,
CanoAbad María F.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12403
Subject(s) - biology , creb , microbiology and biotechnology , apoptosis , mapk/erk pathway , kinase , biochemistry , transcription factor , gene
Summary The mutated form of the Ca 2+ channel CALHM 1 (Ca 2+ homeostasis modulator 1), P86L‐ CALHM 1, has been correlated with early onset of Alzheimer's disease ( AD ). P86L‐ CALHM 1 increases production of amyloid beta (Aβ) upon extracellular Ca 2+ removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM 1 and P86L‐ CALHM , upon Aβ treatment, on the following: (i) the intracellular Ca 2+ signal pathway; (ii) cell survival proteins ERK 1/2 and Ca 2+ / cAMP response element binding ( CREB ); and (iii) cell vulnerability after treatment with Aβ. Using aequorins to measure the effect of nuclear Ca 2+ concentrations ([Ca 2+ ] n ) and cytosolic Ca 2+ concentrations ([Ca 2+ ] c ) on Ca 2+ entry conditions, we observed that baseline [Ca 2+ ] n was higher in CALHM 1 and P86L‐ CALHM 1 cells than in control cells. Moreover, exposure to Aβ affected [Ca 2+ ] c levels in HeLa cells overexpressing CALHM 1 and P86L‐ CALHM 1 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‐ CALHM 1‐overexpressing cells than in CALHM 1 or control cells. These results suggest that in the presence of Aβ, P86L‐ CALHM 1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro‐cytotoxic pathways, thus potentially contributing to its deleterious effects in AD .