ITPR3

ITPR3 Background

The ITPR3 gene encodes inositol 1,4,5-trisphosphate receptor type 3, one of intracellular calcium (Ca2⁺) release channels mediates the calcium signaling ^[1][2]. The IP3R proteins are structurally and functionally divided into 5 distinct domains: the N-terminal coupling domain (or suppressor domain), the IP3-binding core, the modulatory and transducing domain, the channel domain and the C-terminal coupling domain ^[3]. Among the three IP3R isoforms, IP3R3 has the lowest affinity for IP3 ^[4]. The binding of IP3R and IP3R3 redistributes Ca2⁺ from the ER to cytosol, leading to an increase in the cytosolic Ca2⁺ concentration ^[5]. Elevated Ca2⁺ levels further activates Ca2⁺-dependent proteins, inducing a cascade of intracellular responses, including cell division, cell proliferation, apoptosis, fertilization, development, behavior, memory, and learning ^[6]. IP3R3 was shown to correlate with colorectal carcinoma aggressiveness ^[7], or with increased cell migration capacities ^[8]. Inhibition of the IP3R3 attenuated breast cancer cell proliferation ^[9], migration, invasion, and survival of glioblastoma cells ^[10] and revealed an oscillating Ca2⁺ signature along with a slowing down cell migration in human breast cancer cells ^[8]. IP3R3 may also be specifically involved in gastric cancer peritoneal dissemination and these receptors may serve as a molecular target for treatment of this cancer ^[11]. On the other hand, inhibition of the IP3R3 degradation resulted in sensitization to photodynamic therapy in tumors with no or low levels of phosphatase and tensin homologue (PTEN) expression ^[12]. Ingeborg Rezuchova et al. clearly proved that in tumor cells of solid tumors, the IP3R3 has anti-apoptotic and proliferative function, on contrary to the IP3R1 and IP3R2 ^[13].

[1] Yamamoto-Hino M, Sugiyama T, et al. Cloning and characterization of human type 2 and type 3 inositol 1,4,5-trisphosphate receptors [J]. Recept. Channels. 1994, 2 (1): 9-22.
[2] Blondel O, Takeda J, et al. Sequence and functional characterization of a third inositol trisphosphate receptor subtype, IP3R-3, expressed in pancreatic islets, kidney, gastrointestinal tract, and other tissues [J]. J Biol Chem. 1993;268:11356-11363.
[3] Bosanac I, Michikawa T, et al. Structural insights into the regulatory mechanism of IP3 receptor [J]. Biochim Biophys Acta. 2004;1742:89-102.
[4] Newton CL, Mignery GA, et al. Co-expression in vertebrate tissues and cell lines of multiple inositol 1,4,5-trisphosphate (InsP3) receptors with distinct affinities for InsP3 [J]. J Biol Chem. 1994;269:28613-28619.
[5] Berridge M.J. Inositol trisphosphate and calcium signalling [J]. Nature. 1993; 361: 315-325.
[6] Furuichi T. and Mikoshiba K. Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain [J]. J. Neurochem. 1995; 64: 953-960.
[7] Shibao, K. et al. The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma [J]. Cell Calcium 2010, 48, 315-323.
[8] Mound, A. et al. Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal [J]. Oncotarget 2017, 8, 72324-72341.
[9] Szatkowski, C., Parys, J. B., Ouadid-Ahidouch, H. & Matifat, F. Inositol 1,4,5-trisphosphate-induced Ca2+ signalling is involved in estradiol-induced breast cancer epithelial cell growth [J]. Mol. Cancer 2010, 9, 156.
[10] Kang, S. S. et al. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival [J]. Cancer Res. 2010, 70, 1173-1183.
[11] Sakakura, C. et al. Possible involvement of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers [J]. Anticancer Res. 2003, 23, 3691-3697.
[12] Kuchay, S. et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth [J]. Nature 2017, 546, 554-558.
[13] Ingeborg Rezuchova, Sona Hudecova, et al. Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells [J]. Rezuchova et al. Cell Death and Disease (2019) 10:186.