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

• Published in: Aging cell 2015-12, Vol.14 (6), p.1094-1102
• Main Authors: Moreno‐Ortega, Ana José, Buendia, Izaskun, Mouhid, Lamia, Egea, Javier, Lucea, Susana, Ruiz‐Nuño, Ana, López, Manuela G., Cano‐Abad, María F.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Antibodies - immunology; Apoptosis - physiology; Ca2+ channel CALHM1; Ca2+ homeostasis; Calcium - metabolism; Calcium Channels - genetics; Calcium Channels - immunology; Calcium Channels - metabolism; Caspase 3 - metabolism; Caspase 7 - metabolism; caspases; Cell death; Cell Line, Tumor; Cell Survival - genetics; CREB; Cyclic AMP Response Element-Binding Protein - metabolism; early apoptosis; Extracellular Signal-Regulated MAP Kinases - metabolism; Genetic aspects; HeLa Cells; Homeostasis; Humans; Ion Transport - genetics; MAP Kinase Signaling System - genetics; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mitogens; Neurons; Original; Polymorphism, Single Nucleotide - genetics; Protein kinases
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12403

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.