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

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.