Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress

Abstract

CALHM1 (calcium homoeostasis modulator 1), a membrane protein with similarity to NMDA (N-methyl-D-aspartate) receptor channels that localizes in the plasma membrane and the ER (endoplasmic reticulum) of neurons, has been shown to generate a plasma-membrane Ca(2+) conductance and has been proposed to influence Alzheimer's disease risk. In the present study we have investigated the effects of CALHM1 on intracellular Ca(2+) handling in HEK-293T [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] cells by using targeted aequorins for selective monitorization of Ca(2+) transport by organelles. We find that CALHM1 increases Ca(2+) leak from the ER and, more importantly, reduces ER Ca(2+) uptake by decreasing both the transport capacity and the Ca(2+) affinity of SERCA (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase). As a result, the Ca(2+) content of the ER is drastically decreased. This reduction in the Ca(2+) content of the ER triggered the UPR (unfolded protein response) with induction of several ER stress markers, such as CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein], ERdj4, GRP78 (glucose-regulated protein of 78 kDa) and XBP1 (X-box-binding protein 1). Thus CALHM1 might provide a relevant link between Ca(2+) homoeostasis disruption, ER stress and cell damage in the pathogenesis of neurodegenerative diseases.

Structural and Functional Similarities of Calcium Homeostasis Modulator 1 (CALHM1) Ion Channel with Connexins, Pannexins, and Innexins*

“…Cortical neurons from mice with Calhm1 genetically deleted have altered electrophysiological properties and fail to respond to reduced [Ca 2ϩ ] o (3). Notably, CALHM1 is permeable to Ca 2ϩ (1,3) and may also participate in cytoplasmic Ca 2ϩ homeostasis (1,(3)(4)(5). The ion permeability properties of CALHM1 are unique: Ca 2ϩ is only 10-fold selected for over Na ϩ (P Ca /P Na ϳ11), CALHM1 does not discriminate between Na ϩ and K ϩ , and it allows significant monovalent anion permeation (P Cl /P Na ϳ0.5) (3).…”

CALHM1 controls the Ca2+-dependent MEK, ERK, RSK and MSK signaling cascade in neurons

“…A suggestive similarity with the topology of ionotropic glutamate receptors, however, raised the possibility that CALHM1 might function as a Ca 2+ channel component (Dreses-Werringloer et al, 2008). The first evidence that CALHM1 could fulfill this role came from the observation that CALHM1 overexpression in different cell lines increases cytoplasmic Ca 2+ levels by facilitating Ca 2+ entry into the cells (Dreses-Werringloer et al, 2008;Gallego-Sandín et al, 2011;Moreno-Ortega et al, 2010). Furthermore, electrophysiological studies demonstrated that CALHM1 induces a novel plasma membrane Ca 2+ selective current (Dreses-Werringloer et al, 2008).…”

Astroglial calcium signalling in Alzheimer's disease

“…There are certain arguments that β-amyloid excitotoxicity is mediated by extra-synaptic NMDA receptors [16], although this might be an indirect effect (for example, through an inhibition of astroglial glutamate clearance systems [17]). Polymorphism of the encoding gene of the recently identified Ca 2+ homeostasis modulator 1 channel (CALHM1), which is present in neuronal plasmalemma and endomembranes [18,19], has been associated with some forms of AD [20]; the aberrant form of CALHM1 arguably deregulated neuronal Ca 2+ homeostasis [21,22]. In the animal models bearing AD-associated mutations of presenilins, depletion of the ER Ca 2+ stores and modification of inositol 1,4,5 trisphosphate (InsP 3 ) receptors gating are a common finding [23,24].…”