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

Sonia Gallego-Sandin , Maria Teresa Alonso , Javier Garcia-Sancho (1)

1 IBGM, University of Valladolid

Calcium homeostasis modulator 1 (CALHM1), a membrane protein with similarity to NMDA receptor channels that localizes in the plasma membrane and the endoplasmic reticulum (ER)of neurons, has been shown to generate a plasma membrane Ca2+ conductance and has been proposed to influence Alzheimer Disease risk. In the present study we have investigated the effects of CALHM1 on intracellular Ca2+ handling in HEK293T cells by using targeted aequorins for selective monitorization of Ca2+ transport by organelles. We find that CALHM1 increases Ca2+ leak of the ER and, more importantly, reduces ER Ca2+ uptake by decreasing both the transport capacity and the Ca2+ affinity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). As a result, the Ca2+ content of the ER is drastically decreased. This reduction of the Ca2+ content of the ER triggered the unfolded protein response (UPR) with induction of several ER stress markers, such as CHOP, ERdj4, GRP78 and XBP1. Thus, CALHM1 might provide a relevant link between Ca2+ homeostasis disruption, ER stress and cell damage in the pathogenesis of neurodegenerative diseases.

Mots clés: Life Sciences

Sonia Gallego-Sandin, Maria Teresa Alonso, Javier Garcia-Sancho. Calcium homeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress. Biochemical Journal, 2011, 437 (3), pp.469-475. ⟨10.1042/BJ20110479⟩. ⟨hal-00608392⟩