title: CALHM1 and its polymorphism P86L differentially control Ca²⁺homeostasis, mitogen-activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β.
abstract: 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.
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.|Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana José
authors.initials: AJ
authors.lastname: Moreno-Ortega
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Lamia
authors.initials: L
authors.lastname: Mouhid
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.|Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Lucea
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.|Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Nuño
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.|Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.|Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: María F
authors.initials: MF
authors.lastname: Cano-Abad
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; C530077:CALHM1 protein, human; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053179:Caspase 7; D002118:Calcium
keywords: Alzheimer's disease; CREB; Ca2+ channel CALHM1; Ca2+ homeostasis; caspases; early apoptosis