New Insights in the IP₃ Receptor and Its Regulation

The inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) is a Ca²⁺-release channel mainly located in the endoplasmic reticulum (ER). Three IP₃R isoforms are responsible for the generation of intracellular Ca²⁺ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP₃R and try to link these data with the newest information concerning IP₃R activation and regulation. A special focus of this review will be directed towards the regulation of the IP₃R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca²⁺-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP₃R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP₃R-mediated Ca²⁺ signaling in cancer treatment.