Itpr2, short for inositol 1,4,5-trisphosphate receptor, type 2, is an endoplasmic reticulum calcium-release channel. It plays a crucial role in calcium fluxes from the ER to the mitochondria, which are involved in various biological processes such as cellular senescence, myelination, and the regulation of mitochondrial-ER contacts [1,2]. The function of Itpr2 is also associated with the regulation of Ca2+ homeostasis in oligodendrocytes and is potentially involved in related signal pathways like MAPK/ERK-CDK6/cyclin D1 axis [2].

In Itpr2 knockout (KO) mice, improved aging was observed, including increased lifespan, better response to metabolic stress, less immunosenescence, and reduced liver steatosis and fibrosis. Cellular senescence was decreased in these KO mice and their embryo-derived cells. Ablation of ITPR2 decreased the number of contacts between the mitochondria and the ER, while forced contacts induced premature senescence, suggesting its role in regulating senescence and aging [1]. In OL-specific Itpr2 KO adolescent mice, Ca2+ homeostasis was disturbed, myelination was inhibited, and they showed anxiety/depressive-like behaviors due to interrupted OPC proliferation [2]. Astrocytic calcium-deficient Itpr2-/-mice displayed abnormal resting-state functional connectivity in depression-related networks [3].

In conclusion, Itpr2 is essential for maintaining normal calcium-related biological functions. Studies using Itpr2 KO mouse models have revealed its significance in cellular senescence, aging, myelination, and mental-disorder-related processes such as depression. These findings provide insights into potential therapeutic strategies for age-related pathologies and myelin-associated psychiatric disorders.

References:

1. Ziegler, Dorian V, Vindrieux, David, Goehrig, Delphine, Martin, Nadine, Bernard, David. 2021. Calcium channel ITPR2 and mitochondria-ER contacts promote cellular senescence and aging. In Nature communications, 12, 720. doi:10.1038/s41467-021-20993-z. https://pubmed.ncbi.nlm.nih.gov/33526781/

2. Zhang, Ming, Zhi, Na, Feng, Jiaxiang, Wu, Shengxi, Zhao, Xianghui. 2024. ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive-Like Behavior in Adolescent Mice. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2306498. doi:10.1002/advs.202306498. https://pubmed.ncbi.nlm.nih.gov/38476116/

3. Liu, Jiaming, Mo, Jia-Wen, Wang, Xunda, Feng, Yanqiu, Cao, Xiong. 2022. Astrocyte dysfunction drives abnormal resting-state functional connectivity in depression. In Science advances, 8, eabo2098. doi:10.1126/sciadv.abo2098. https://pubmed.ncbi.nlm.nih.gov/36383661/