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

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Endoplasmic Reticulum Stress in Health and Disease

Abstract

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.

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Abbreviations

BI1:

Bax inhibitor-1

BiP:

Immunoglobulin heavy chain binding protein

CaMKII:

Calmodulin-dependent protein kinase II

cyt c:

Cytochrome c

eIF2α:

Eukaryotic initiation factor 2α

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

ERO1α:

ER oxidoreductin 1α

FAD:

Familial Alzheimers disease

GRP:

Glucose-regulated protein

HO-1:

Heme oxygenase 1

IMM:

Inner mitochondrial membrane

IP3 :

Inositol 1,4,5-trisphosphate

IP3Rs:

Inositol 1,4,5-trisphosphate receptors

JNK:

C-Jun N-terminal kinase

MAMs:

mitochondria associated membranes

MCU:

Mitochondrial Ca2+ uniporter

mTOR:

Mammalian target of rapamycin

NPR:

NADPH-P450 reductase

OMM:

Outer mitochondrial membrane

P450:

Cytochrome P450

PDI:

Protein disulfide isomerase

PLC:

Phospholipase C

PML:

Promyelocytic leukemia

PTP:

Permeability transition pore

ROS:

Reactive oxygen species

RyRs:

Ryanodine receptors

SERCA:

Sarco- and endoplasmic reticulum Ca2+ ATPase

SERCA1 T:

Truncated sarco- and endoplasmic reticulum Ca2+ ATPase 1

SPCA1:

Secretory pathway Ca2+ ATPase 1

STIM:

Stromal interaction molecule

TRP:

Transient receptor potential

TRPC6:

Canonical transient receptor potential-6

UPR:

Unfolded protein response

VDAC:

Voltage dependant anion channel

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Acknowledgments

The authors wish to thank the Research Council of the K.U. Leuven and the Research Foundation – Flanders (F.W.O.) for their support of the research work performed in their lab. We also wish to apologize to those whose research papers in this field were not included in this book chapter. We also wish to thank our national and international collaborators in this field for fruitful discussions.

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  1. Department of Cellular and Molecular Medicine, Laboratory of Molecular and Cellular Signaling, Campus Gasthuisberg O/N-1 bus 802, Herestraat 49, 3000, Leuven, BE, Belgium

    Tim Vervliet, Santeri Kiviluoto & Geert Bultynck

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  1. Tim Vervliet
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  2. Santeri Kiviluoto
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  3. Geert Bultynck
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Correspondence to Geert Bultynck .

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Editors and Affiliations

  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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© 2012 Springer Science+Business Media Dordrecht

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Vervliet, T., Kiviluoto, S., Bultynck, G. (2012). ER Stress and UPR Through Dysregulated ER Ca2+ Homeostasis and Signaling. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_5

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