{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ITPRID2 is a cytoskeletal‐associated regulator of inositol 1,4,5‐trisphosphate receptors (IP₃Rs) that plays a critical role in organizing and “licensing” IP₃R–mediated Ca²⁺ signaling. In multiple studies, the protein—also known under the alias of KRAS‐induced actin‐interacting protein (KRAP)—has been shown to physically associate with IP₃Rs, thereby ensuring their correct subcellular localization in diverse tissues such as liver, pancreas, stomach, kidneys, and even in certain lymphoid cells. This spatial control is crucial for proper IP₃R function, as it facilitates efficient Ca²⁺ release upon stimulation without altering the overall Ca²⁺ storage in endoplasmic reticulum compartments."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Detailed mapping of the molecular determinants has revealed that specific highly conserved regions in ITPRID2 are indispensable for its interaction with IP₃Rs. Mutational analyses demonstrate that disruption of key amino-acid residues abrogates the binding and consequently disturbs IP₃R localization, which in turn impairs Ca²⁺ signaling dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its scaffold role, ITPRID2 expression is itself modulated by upstream transcriptional regulators such as CREB; through this control, the protein contributes to the maintenance of IP₃R expression and positioning. Such regulation has implications not only for Ca²⁺ release but also for downstream signaling cascades – for instance, in metabolic as well as exocrine tissues where appropriate Ca²⁺ signaling is essential for normal physiological function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n The functional impact of ITPRID2 is further underscored by studies linking its dysregulation to metabolic abnormalities. In ITPRID2-deficient models, altered IP₃R localization perturbs Ca²⁺ fluxes, which has been associated with enhanced metabolic rate, modified pancreatic enzyme secretion, and resistance to diet-induced metabolic dysfunctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ITPRID2 functions as a key adaptor protein that couples the actin cytoskeleton with IP₃R signaling machinery. By securing the proper subcellular distribution of IP₃Rs, it ensures efficient Ca²⁺ release in response to external and internal cues, thereby influencing diverse cellular processes including metabolism, secretion, and even aspects of tumor-related signaling.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takahiro Fujimoto, Takashi Machida, Toshiyuki Tsunoda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KRAS-induced actin-interacting protein regulates inositol 1,4,5-trisphosphate-receptor-mediated calcium release."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.03.112"}], "href": "https://doi.org/10.1016/j.bbrc.2011.03.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21457704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21457704"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Takahiro Fujimoto, Takashi Machida, Yoko Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KRAS-induced actin-interacting protein is required for the proper localization of inositol 1,4,5-trisphosphate receptor in the epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.03.065"}], "href": "https://doi.org/10.1016/j.bbrc.2011.03.065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21420385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21420385"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Takahiro Fujimoto, Takashi Machida, Toshiyuki Tsunoda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Determination of the critical region of KRAS-induced actin-interacting protein for the interaction with inositol 1,4,5-trisphosphate receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.04.016"}], "href": "https://doi.org/10.1016/j.bbrc.2011.04.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21501587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21501587"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Vikas Arige, Lara E Terry, Sundeep Malik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CREB regulates the expression of type 1 inositol 1,4,5-trisphosphate receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.258875"}], "href": "https://doi.org/10.1242/jcs.258875"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34533188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34533188"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takahiro Fujimoto, Senji Shirasawa "}, {"type": "b", "children": [{"type": "t", "text": "Identification of KRAP-expressing cells and the functional relevance of KRAP to the subcellular localization of IP3R in the stomach and kidney."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2012.1126"}], "href": "https://doi.org/10.3892/ijmm.2012.1126"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22992961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22992961"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Takahiro Fujimoto, Kyoko Miyasaka, Midori Koyanagi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0004240"}], "href": "https://doi.org/10.1371/journal.pone.0004240"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19156225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19156225"}]}]}]}