Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival

Cell-death and -survival decisions are critically controlled by intracellular Ca2+ homeostasis and dynamics at the level of the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) play a pivotal role in these processes by mediating Ca2+ 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 Ca2+ 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 (IP(3)R1, IP(3)R2 and IP(3)R3) control cell death and survival. First, we will present an overview of the isoform-specific regulation of IP(3)Rs by cellular factors like IP3, Ca2+, Ca2+-binding proteins, adenosine triphosphate (ATP), thiol modification, phosphotylation and interacting proteins, and of IP3R-isoform specific expression patterns. Second, we will discuss the role of the ER as a Ca2+ store in cell death and survival and how IP(3)Rs and pro-survival/pro-death proteins can modulate the basal ER Ca2+ leak. Third, we will review the regulation of the Ca2+-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. (C) 2014 Elsevier B.V. All rights reserved.