CALHM1 and its polymorphism P86L differentially control Ca<sup>2+</sup> homeostasis, mitogen-activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β
Entity
UAM. Departamento de Farmacología; Instituto de Investigación del Hospital de La Princesa (IP)Publisher
Anatomical Society; John Wiley & Sons Ltd.Date
2015-12-01Citation
10.1111/acel.12403
Aging Cell 14.6 (2015): 1094-1102
ISSN
1474-9718; 1474-9726 (online)DOI
10.1111/acel.12403Funded by
This work was partly supported by the following grants: Ministerio de Economía y Competitividad, FPU Program, Refs. AP2009/0343 (AJMO) and AP2010/1219 (IB). ARN: FIS PI10/01426. MGL: Ministerio de Economía y Competitividad, Ref. SAF2012-23332. MFCA: Consolidación de grupos de investigación UAM-CAM 1004040047. We also thank Fundación Teófilo Hernando, Madrid, Spain, for their continued supportProject
Gobierno de España. AP2009/0343; Gobierno de España. AP2010/1219; Gobierno de España. PI10/01426.; Gobierno de España. SAF2012-23332; Gobierno de España. FIS PI10/01426Editor's Version
http://dx.doi.org/10.1111/acel.12403Subjects
Alzheimer’s disease; Ca2+ channel CALHM1; CREB; Ca2+ homeostasis; Caspases; Early apoptosis; MedicinaRights
© 2015 The AuthorsAbstract
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 (Ab) 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
Ab 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 Ab. 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 Ab affected [Ca2+]c
levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1
compared with control cells. Treatment with Ab 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 Ab, 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.
Files in this item
Google Scholar:Moreno-Ortega, Ana José
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Buendía, Izaskun
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Mouhid, Lamia
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Egea, Javier
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Lucea, Susana
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Ruiz-Nuño, Ana
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López, Manuela G.
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Cano Abad, María Francisca
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