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 (IP 3 ) receptors (IP 3 Rs) 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 IP 3 R channels, which can happen in an IP 3 R-isoform-dependent manner. In this review, we will focus on how the different IP 3 R 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 IP 3 , Ca 2 + , Ca 2 + -binding proteins, adenosine triphosphate (ATP), thiol modification, phosphorylation and interacting proteins, and of IP 3 R-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 IP 3 Rs 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 IP 3 R 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 IP 3 R 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.