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.
Vanmunster et al. (Mon,) studied this question.
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