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) activity. IP3Rs are channels for Ca2+ redistribution from the endoplasmic reticulum (ER) to the cytosol and other organelles, and Itprid2 licenses IP3Rs to release Ca2+ to the cytosol and mitochondria [1]. It is also involved in stabilizing ER-mitochondrial junctions, which are important for Ca2+ transfer between these organelles [1]. This regulation of Ca2+ signaling by Itprid2 is essential for various cellular processes such as cell survival, adaptation, and death [3].

In Itprid2 (KRAP)-deficient mice, there are altered whole-body energy metabolism and resistance to diet-induced obesity and diabetes, suggesting its role in metabolism-related diseases [2]. Loss of Itprid2 in cells abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors, indicating its essentiality in normal Ca2+ signaling [1]. Reduction of Itprid2 protein by siRNA in cultured HEK293 or MCF7 cells diminishes ATP-induced Ca2+ release, further demonstrating its role in IP3R-mediated Ca2+ release [4].

In conclusion, Itprid2 is vital for regulating IP3R-mediated Ca2+ signaling and maintaining normal cellular Ca2+ homeostasis. The study of Itprid2-deficient mouse models has revealed its potential significance in metabolism-related diseases, highlighting its potential as a target for understanding and treating such conditions.

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. 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/