ITPR2

ITPR2 Background

The ITPR2 encodes inositol 1,4,5-trisphosphate receptor type 2 (known as IP3R2), 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.

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[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.
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[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.