title: Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival.
abstract: Cell-death and -survival decisions are critically controlled by intracellular Ca(2+) homeostasis and dynamics at the level of the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a pivotal role in these processes by mediating Ca(2+) flux from the ER into the cytosol and mitochondria. Hence, it is clear that many pro-survival and pro-death signaling pathways and proteins affect Ca(2+) signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. In this review, we will focus on how the different IP3R isoforms (IP3R1, IP3R2 and IP3R3) control cell death and survival. First, we will present an overview of the isoform-specific regulation of IP3Rs by cellular factors like IP3, Ca(2+), Ca(2+)-binding proteins, adenosine triphosphate (ATP), thiol modification, phosphorylation and interacting proteins, and of IP3R-isoform specific expression patterns. Second, we will discuss the role of the ER as a Ca(2+) store in cell death and survival and how IP3Rs and pro-survival/pro-death proteins can modulate the basal ER Ca(2+) leak. Third, we will review the regulation of the Ca(2+)-flux properties of the IP3R isoforms by the ER-resident and by the cytoplasmic proteins involved in cell death and survival as well as by redox regulation. Hence, we aim to highlight the specific roles of the various IP3R isoforms in cell-death and -survival signaling. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Hristina
authors.initials: H
authors.lastname: Ivanova
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Vervliet
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address: Humbert.DeSmedt@med.kuleuven.be.
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.affiliation: KU Leuven Lab. of Molecular and Cellular Signaling, Dept. of Cellular and Molecular Medicine, Campus Gasthuisberg O&N I Box 802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address: Geert.Bultynck@med.kuleuven.be.
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016923:Cell Death; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006706:Homeostasis; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
keywords: Apoptosis; Autophagy; Ca(2+) signaling; Cell fate; ER stress; IP(3) receptor