IP Receptor Properties and Function at Membrane Contact Sites.

The inositol 1,4,5-trisphosphate (IP) receptor (IPR) is a ubiquitously expressed Ca-release channel localized in the endoplasmic reticulum (ER). The intracellular Ca signals originating from the activation of the IPR 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 IPRs in these two processes does not only depend on their activity, which is modulated by the cytosolic composition (Ca, 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, Ca microdomains are formed, in which the Ca concentration is finely regulated by the different ER, mitochondrial and lysosomal Ca-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 Ca signaling in general, and of the IPR in particular, in the control of basal mitochondrial bioenergetics, apoptosis, and autophagy at the level of inter-organellar contact sites.