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

Abstract

SummaryThe 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.

RETRACTED ARTICLE: Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial-mesenchymal Transition in Hepatocellular Carcinoma

“…4A2 ). Growing evidence has showed that ERK signaling is crucial for progression of HCC 18 , 19 , and its activation can be triggered by changing cytosolic Ca 2+ level 9 , 20 . As Sorcin also regulates Ca 2+ homeostasis, so we focus on exploring whether Sorcin enhanced metastasis by activating ERK signaling in HCC.…”

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Besides, depletion of the Ca 2+ homeostasis modulator 1 (CALHM1), a Ca 2+ channel involved in the regulation of cytosolic Ca 2+ levels, was found to downregulate ROS production, to increase the expression of HIF-1α and to display neuroprotective effects against ischemia in mice [ 164 ]. Notably, the mutation of this channel (P86L-CALHM1) got associated with Alzheimer's disease and mitochondrial Ca 2+ overload, potentially causing increased vulnerability of these cells to apoptotic stimuli [ [165] , [166] , [167] ].…”

Calcium homeostasis modulator (CALHM) ion channels

“…A meta-analysis suggested that the hCALHM1-P86L polymorphism is not an independent risk factor for LOAD but is associated with the age of onset [17]. Studies in mammalian cells showed that the P86L variant caused a partial inhibition of the effect of CALHM1 on Ca 2+ influx and amyloid-beta (Aβ) metabolism [9, 26, 34, 43]. However, no differences were observed in the gating and permeation properties between wild type (WT) and P86L-CALHM1 expressed in Xenopus oocytes or N2A cells, suggesting that the P86L polymorphism does not affect the intrinsic biophysical properties of hCALHM1 channels [20].…”

“…Exogenous expression of CALHM1 or P86L-CALHM1 elevated basal [Ca 2+ ] i [11, 26, 36]. In contrast, the magnitude of the Ca 2+ add-back response measured in cell populations was reduced in cells transiently expressing P86L-CALHM1 [8, 9, 26, 36].…”

“…In contrast, the magnitude of the Ca 2+ add-back response measured in cell populations was reduced in cells transiently expressing P86L-CALHM1 [8, 9, 26, 36]. Nevertheless, when measured at the single-cell level, the magnitude of the response was not different in some studies [11, 36].…”