Geert Bultynck

ER Stress and UPR Through Dysregulated ER Ca2+ Homeostasis and Signaling

The endoplasmic reticulum (ER) has two important biological functions: protein folding and storing intracellular Ca2+. Importantly, adequate ER Ca2+-store filling is critical for proper protein folding. In many occasions, ER stress is tightly linked to disruption of ER Ca2+ homeostasis, causing the activation of an integrated signaling pathway, the unfolded protein response (UPR). In this book chapter, we will review the ER as a dynamic intracellular Ca2+-storage organelle in a constant state of Ca2+flux that is in close proximity to the mitochondria, thereby controlling cell survival, adaptive responses to stress and apoptosis. Next, we will discuss how altered [Ca2+]ER homeostasis leads to ER stress, and how ER stress and their sensors alters Ca2+ flux. Recent studies provided novel insights in the molecular mechanisms underlying these processes, including a dynamic regulation of ER Ca2+-uptake and –release mechanisms by ER chaperones and the main controller of the ER-stress sensors, GRP78/BiP. Furthermore, recently identified Ca2+-transport systems also seem to target ER-stress proteins. Overall, it is clear that altered Ca2+ signaling and UPR during ER stress are closely related through dynamic physical interactions between their key players.

Interfering with intramolecular loop/tail-interactions influences Cx43-hemichannel activity

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