Itprid2, also known as Kras-induced actin-interacting protein (KRAP), is a cytoplasmic protein associated with filamentous-actin (F-actin) [2]. It plays a crucial role in regulating inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated calcium release. IP3Rs are high-conductance channels that redistribute Ca2+ from the endoplasmic reticulum (ER) to the cytosol and other organelles. KRAP licenses IP3Rs to release Ca2+ to the cytosol and mitochondria, and also stabilizes ER-mitochondrial junctions [1]. This regulation of Ca2+ transfer is important in various biological processes, including cell-fate decisions such as cell survival, adaptation, and death [3].

KRAP-deficient mice show altered whole-body energy metabolism and resistance to diet-induced obesity and diabetes, suggesting its role in metabolism-related diseases [2]. Reduction of KRAP protein by KRAP-specific siRNA in cultured HEK293 or MCF7 cells diminishes ATP-induced Ca2+ release, indicating that KRAP regulates IP3R-mediated Ca2+ release [5]. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors, and also reduces the number of ER-mitochondrial membrane contact sites [1]. Over-expressing KRAP immobilizes additional IP3R clusters and results in more Ca2+ puffs and larger global Ca2+ signals [4].

In conclusion, Itprid2 (KRAP) is essential for regulating IP3R-mediated calcium release and ER-mitochondrial junctions, which impacts various biological processes. The study of Itprid2 using gene-knockout models, such as KRAP-deficient mice, has revealed its role in metabolism-related diseases, highlighting its potential as a target for further research and therapeutic intervention in these disease areas.

References:

1. Atakpa-Adaji, Peace, Ivanova, Adelina, Kujawa, Karolina, Taylor, Colin W. 2024. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions. In Journal of cell science, 137, . doi:10.1242/jcs.261728. https://pubmed.ncbi.nlm.nih.gov/38786982/

2. Fujimoto, Takahiro, Shirasawa, Senji. . KRAS-induced actin-interacting protein: a potent target for obesity, diabetes and cancer. In Anticancer research, 31, 2413-7. doi:. https://pubmed.ncbi.nlm.nih.gov/21873152/

3. Akl, Haidar, Bultynck, Geert. 2012. Altered Ca(2+) signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. In Biochimica et biophysica acta, 1835, 180-93. doi:10.1016/j.bbcan.2012.12.001. https://pubmed.ncbi.nlm.nih.gov/23232185/

4. Thillaiappan, Nagendra Babu, Smith, Holly A, Atakpa-Adaji, Peace, Taylor, Colin W. 2021. KRAP tethers IP3 receptors to actin and licenses them to evoke cytosolic Ca2+ signals. In Nature communications, 12, 4514. doi:10.1038/s41467-021-24739-9. https://pubmed.ncbi.nlm.nih.gov/34301929/

5. Fujimoto, Takahiro, Machida, Takashi, Tsunoda, Toshiyuki, Kuroki, Masahide, Shirasawa, Senji. 2011. KRAS-induced actin-interacting protein regulates inositol 1,4,5-trisphosphate-receptor-mediated calcium release. In Biochemical and biophysical research communications, 408, 214-7. doi:10.1016/j.bbrc.2011.03.112. https://pubmed.ncbi.nlm.nih.gov/21457704/