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IP3 Receptor Properties and Function at Membrane Contact Sites

  • Gemma Roest
  • Rita M. La Rovere
  • Geert Bultynck
  • Jan B. Parys
Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 981)

Abstract

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a ubiquitously expressed Ca2+-release channel localized in the endoplasmic reticulum (ER). The intracellular Ca2+ signals originating from the activation of the IP3R regulate multiple cellular processes including the control of cell death versus cell survival via their action on apoptosis and autophagy. The exact role of the IP3Rs in these two processes does not only depend on their activity, which is modulated by the cytosolic composition (Ca2+, ATP, redox status, …) and by various types of regulatory proteins, including kinases and phosphatases as well as by a number of oncogenes and tumor suppressors, but also on their intracellular localization, especially at the ER-mitochondrial and ER-lysosomal interfaces. At these interfaces, Ca2+ microdomains are formed, in which the Ca2+ concentration is finely regulated by the different ER, mitochondrial and lysosomal Ca2+-transport systems and also depends on the functional and structural interactions existing between them. In this review, we therefore discuss the most recent insights in the role of Ca2+ signaling in general, and of the IP3R in particular, in the control of basal mitochondrial bioenergetics, apoptosis, and autophagy at the level of inter-organellar contact sites.

Keywords

Apoptosis Autophagy Ca2+ microdomains Cell death Cell survival Endoplasmic reticulum IP3 receptor Lysosomes Membrane contact sites Mitochondria 

Abbreviations

ALS

Amyotrophic lateral sclerosis

AMPK

AMP-activated kinase

ATG

Autophagy-related

BIRD-2

Bcl-2/IP3R disruptor-2 peptide

CICR

Ca2+-induced Ca2+ release

CREB

cAMP response element-binding protein

DT40 TKO

DT40 IP3R triple knock-out

ER

Endoplasmic reticulum

Fis1

Fission 1 homologue

GRP75

Glucose-regulated protein 75

GRP78/BiP

Glucose-regulated protein 78

GSK3β

Glycogen synthase kinase-3β

IMM

Inner mitochondrial membrane

IBC

IP3-binding core

IP3

Inositol 1,4,5-trisphosphate

IP3R

IP3 receptor

LC3

Microtubule-associated protein light chain 3

LRRK2

Leucine-rich repeat kinase 2

MAM

Mitochondria-associated ER membrane

MCU

Mitochondrial Ca2+ uniporter

Mfn

Mitofusin

mPTP

Mitochondrial permeabilization transition pore

mTORC1

Mechanistic target of rapamycin complex 1

OMM

Outer mitochondrial membrane

NAADP

Nicotinic acid adenine dinucleotide phosphate

PACS-2

Phosphofurin acidic cluster sorting protein 2

PERK

Protein kinase RNA-like ER kinase

PIP3

Phosphatidylinositol 3,4,5-trisphosphate

PKB/Akt

Protein kinase B

PML

Promyelocytic leukemia

PTEN

Phosphatase and tensin homolog

PTPIP51

Protein tyrosine phosphatase-interacting protein-51

ROS

Reactive oxygen species

RyR

Ryanodine receptor

SERCA

Sarco-/endoplasmic reticulum Ca2+ ATPase

TCA

Tricarboxylic acid

TFEB

Transcription factor EB

TMX

Thioredoxin-like transmembrane protein

TPC

Two-pore channel

TRPML

Transient receptor potential mucolipin

ULK1/2

Atg1/Unc-51-like kinase 1/2

UPR

Unfolded protein response

VAPB

Vesicle-associated protein B

VDAC

Voltage-dependent anion channel

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Notes

Acknowledgements

GR is recipient of a Ph.D. fellowship of the Research Fund—Flanders (FWO). Work performed in the laboratory of the authors was supported by research grants of the FWO, the Research Council of the KU Leuven and the Interuniversity Attraction Poles Programmes (Belgian Science Policy).

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Authors and Affiliations

  1. 1.Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker InstituutKU LeuvenLeuvenBelgium

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