Control of Inositol 1,4,5-Trisphosphate Receptor Activity by Posttranslational Modifications

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are tetrameric calcium (Ca²⁺) release channels localized in the endoplasmic reticulum (ER), where they regulate cellular function by mediating local and global Ca²⁺ fluxes toward the cytosol, cell membrane, and organelles including mitochondria. Disruptions in these Ca²⁺ signals, whether excessive or diminished, due to alterations in IP₃R function have been implicated in a wide range of diseases and pathophysiological conditions. Consequently, the Ca²⁺-flux properties, protein abundance, and localization of IP₃Rs must be tightly regulated. Various mechanisms, including interactions with accessory proteins, ensure proper IP₃R function across diverse physiological contexts. In this review, we highlight the role of posttranslational modifications (PTMs) in modulating IP₃R activity, including phosphorylation/dephosphorylation, redox modifications, glycosylation, palmitoylation, ubiquitination, proteolysis, and transglutaminase-mediated cross-linking. We discuss not only the functional consequences of these PTMs but also provide structural insights when specific modified IP₃R residues have been identified. Furthermore, whenever possible, we emphasize IP₃R isoform-specific effects of PTMs, offering a nuanced perspective on their regulatory significance.