The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Abstract

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). It displays in many cell types a predominantly perinuclear or even nuclear localization. IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. Interestingly, ATP stimulates IP3R2 independently of the cytosolic [Ca2+]. Furthermore, IP3R2 is modulated by phosphorylation events mediated by e.g. protein kinase A, Ca2+/calmodulin-dependent kinase II and protein kinase C. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP, thereby linking in a new way Ca2+-dependent and cAMP-dependent signalling. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Moreover, IP3R2 expression is driven by IP3-induced Ca2+ release leading to a self-perpetuating system of cardiac hypertrophy. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs.

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

“…In particular, apart from the involvement of the calcineurin–NFAT pathway (Sankar, deTombe, & Mignery, 2014), only few things are known about the transcriptional regulation of ITPR2 expression. Here, we identify RXRA as a transcriptional repressor of ITPR2 and thus provide insights into ITPR2 regulation, which is important for cell fate decisions (Vervloessem et al, 2015). ENCODE ChIP‐seq data and our ChIP experiment point out RXRA as a direct regulator of ITPR2 , although the identified RXRA binding site does not contain AGGTCA sequences which are the most frequent RXRA binding motifs (Evans, & Mangelsdorf, 2014; Sever, & Glass, 2013) and is located in the second intron of ITPR2 rather than in its promoter.…”

“…We recently discovered that the inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum (ER) calcium release channel, critically contributes to the implementation of cellular senescence (Wiel et al, 2014). Whereas ITPR2 activity has been shown to be modulated through protein interaction and post‐translational modification (Vervloessem, Yule, Bultynck, & Parys, 2015), how ITPR2 is regulated at the expression level is unclear. To address this question, we performed a genetic screen for regulators of ITPR2 and thereby identified the retinoid X receptor alpha (RXRA) as a transcriptional repressor of ITPR2.…”

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

“…It is clear that a constitutively increased level of IP 3 , the ligand that activates IP 3 R channels, is needed as well. Of interest, IP 3 R2 channels display the highest IP 3 sensitivity [22] . Thus, the combination of high IP 3 R2-expression levels and constitutive IP 3 signaling makes DLBCL cells particularly addicted to Bcl-2 inhibition of IP 3 Rs at the ER, and thus sensitive to BIRD-2.…”

“…Here, we investigated whether IP 3 R2 levels are the only determinant that dictates the BIRD-2 sensitivity of B-cell cancers. Of note, IP 3 R2 is the IP 3 R isoform that displays the highest sensitivity to its ligand IP 3 [21,22]. Interestingly, B-cell cancers, including DLBCL and CLL, display constitutive B-cell receptor (BCR) signaling [23][24][25].…”

HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

“…In DLBCL, a heterogeneous response to BIRD-2 has been observed. The sensitivity of DLBCL to BIRD-2 could be linked to the expression level of the IP 3 R2, the IP 3 R isoform with the highest sensitivity to IP 3 (Akl et al, 2013a;Ivanova et al, 2014;Vervloessem et al, 2015). Given the important role of Ca 2+ signaling in BIRD-2-induced cell death, we opted to study whether this could be enhanced by a Bcl-2-inhibiting tool that also impacts Ca 2+ signaling by partially inhibiting SERCA Ca 2+ -pump activity, i.e.…”