ITPR2 Research Reagents

ITPR2 Background

The ITPR2 encodes inositol 1,4,5-trisphosphate receptor type 2, one of intracellular calcium release channels mediates the calcium signaling ^[1]. All three IP3R isoforms are tetramers, with each subunit encompassing an N-terminus, six transmembrane domains, and a C-terminal tail ^[2][3]. The N-terminus contains an inositol 1,4,5-trisphosphate (IP3)-binding domain, a suppressor domain that inhibits IP3 binding, and a regulatory domain ^[4]. This regulatory domain contains binding sites for Ca2⁺ and ATP as well as consensus phosphorylation sites ^[2][5][6]. The transmembrane and C-terminal domains are essential for tetramerization of IP3Rs ^[7][8]. The full-length isoforms are 60–70% identical in primary sequence, with the N-terminal ligand-binding and C-terminal channel domains sharing the highest similarity ^[9]. IP3R2 exhibits the highest IP3 binding affinity, followed by IP3R1 and then IP3R3 ^[10][11]. The high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Akl H et al. demonstrated that cancer cells particularly expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using a cell-permeable peptide results in pro-apoptotic Ca2⁺ signaling and cell death ^[12]. The binding of IP3R and IP3R2 redistributes Ca2⁺ from the ER to cytosol, leading to an increase in the cytosolic Ca2⁺ concentration ^[13]. 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 ^[14]. The study of Jeremy Petravicz et al. provides the first functional evidence that IP3R2 is the only IP3R isoform expressed by astrocytes, IP3R2 is not required for neuronal Gq-linked GPCR-mediated Ca2⁺ elevations and removal of astrocyte Ca2⁺ increases has no effect on basal neuronal excitatory activity ^[15]. IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism.

[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].
[2] Michikawa T., Hamanaka H., et al. Transmembrane topology and sites of N-glycosylation of inositol 1,4,5-trisphosphate receptor [J]. J. Biol. Chem. 1994, 269, 9184-9189.
[3] Yoshikawa F., Morita M., et al. Mutational analysis of the ligand binding site of the inositol 1,4,5-trisphosphate receptor [J]. J. Biol. Chem. 1996, 271, 18277-18284.
[4] Yoshikawa F., Iwasaki H., et al. Cooperative formation of the ligand-binding site of the inositol 1,4, 5-trisphosphate receptor by two separable domains [J]. J. Biol. Chem. 1999, 274, 328-334.
[5] Patel S., Joseph S. K., et al. Molecular properties of inositol 1,4,5-trisphosphate receptors [J]. Cell Calcium 1999, 25, 247-264.
[6] Foskett J. K., White C., et al. Inositol trisphosphate receptor Ca2+ release channels [J]. Physiol. Rev. 2007, 87, 593-658.
[7] Mignery G. A. and Sudhof, T. C. The ligand binding site and transduction mechanism in the inositol-1,4,5-triphosphate receptor [J]. EMBO J. 1990, 9, 3893-3898.
[8] Sayers L. G., Miyawaki A., et al. Intracellular targeting and homotetramer formation of a truncated inositol 1,4,5-trisphosphate receptor-green fluorescent protein chimera in Xenopus laevis oocytes: evidence for the involvement of the transmembrane spanning domain in endoplasmic reticulum targeting and homotetramer complex formation [J]. Biochem. J. 1997, 323 (Pt 1), 273-280. Recept. Channels. 1994, 2 (1): 9-22.
[9] Patel S, Joseph SK, et al. Molecular properties of inositol 1,4,5-trisphosphate receptors [J]. Cell Calcium. 1999 Mar;25(3):247-64.
[10] Iwai M., Michikawa T., et al. Molecular Basis of the Isoform-specific Ligand-binding Affinity of Inositol 1,4,5-Trisphosphate Receptors [J]. J. Biol. Chem. 2007, 282, 12755-12764.
[11] Iwai M., Tateishi Y., Molecular cloning of mouse type 2 and type 3 inositol 1,4,5-trisphosphate receptors and identification of a novel type 2 receptor splice variant [J]. J. Biol. Chem. 2005, 280, 10305-10317.
[12] Akl H, Monaco G, et al. IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2 [J]. Cell Death Dis. 2013 May 16;4:e632.
[13] Berridge M.J. Inositol trisphosphate and calcium signalling [J]. Nature. 1993; 361: 315-325.
[14] Furuichi T. and Mikoshiba K. Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain [J]. J. Neurochem. 1995; 64: 953-960.
[15] Jeremy Petravicz, Todd A. Fiacco, et al. Loss of IP3Receptor-Dependent Ca2+ Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity [J]. The Journal of Neuroscience, 2008, 28(19):4967-4973.