Abstract
The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a Ca2+-release channel mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms are responsible for the generation of intracellular Ca2+ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP3R and try to link these data with the newest information concerning IP3R activation and regulation. A special focus of this review will be directed towards the regulation of the IP3R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca2+-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP3R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP3R-mediated Ca2+ signaling in cancer treatment.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
10.1 Introduction
The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a ubiquitously expressed Ca2+-release channel mainly located in the endoplasmic reticulum (ER) [1]. The IP3R is activated by IP3, produced by phospholipase C (PLC), following cell stimulation by for instance extracellular agonists, hormones, growth factors or neurotransmitters. The IP3R is responsible for the initiation and propagation of complex spatio-temporal Ca2+ signals that control a multitude of cellular processes [2, 3]. Moreover, dysfunction of the IP3R and deregulation of the subsequent Ca2+ signals is involved in many pathological situations [4,5,6,7,8,9,10].
There are at least three main reasons for the central role of the IP3R in cellular signaling. First, IP3R signaling is not only dependent on the production of IP3, but is also heavily modulated by its local cellular environment, integrating multiple signaling pathways. Indeed, IP3R activity is controlled by the cytosolic and the intraluminal Ca2+ concentrations, pH, ATP, Mg2+ and redox state, as well as by its phosphorylation state at multiple sites. Furthermore, a plethora of associated proteins can modulate localization and activity of the IP3R [11,12,13,14,15]. Second, in higher organisms, three genes (ITPR1, ITPR2 and ITPR3) encode three isoforms (IP3R1, IP3R2, and IP3R3). These isoforms have a homology of about 75% at the a.a. level, allowing for differences in sensitivity towards IP3 (IP3R2 > IP3R1 > IP3R3) as well as towards the various regulatory factors and proteins [12, 16,17,18,19]. Splice isoforms and the possibility to form both homo- and heterotetramers further increase IP3R diversity. Third, the intracellular localization of the IP3Rs determines their local effect [1]. Recently, an increased appreciation for the existence and functional importance of intracellular Ca2+ microdomains was obtained, e.g. between ER and mitochondria, lysosomes or plasma membrane where IP3-induced Ca2+ release (IICR) occurs, allowing Ca2+ to control very local processes [20,21,22,23,24].
As a number of excellent reviews on various aspects of IP3R structure and function have recently appeared [25,26,27,28,29,30,31,32], we will in present review highlight the most recent advances concerning the understanding of IP3R structure and regulation, with special focus on recent insights obtained in relation to IP3R modulation by associated proteins.
10.2 New Structural Information on the IP3R
The IP3Rs form large Ca2+-release channels consisting of 4 subunits, each about 2700 a.a. long, that assemble to functional tetramers with a molecular mass of about 1.2 MDa. Each subunit consists of five distinct domains (Fig. 10.1a): the N-terminal coupling domain or suppressor domain (for IP3R1: a.a. 1–225), the IP3-binding core (IBC, a.a. 226–578), the central coupling domain or modulatory and transducing domain (a.a. 579–2275), the channel domain with 6 trans-membrane helices (a.a. 2276–2589) and the C-terminal tail or gatekeeper domain (a.a. 2590–2749) [33].
The crystal structure of the two N-terminal domains of the IP3R1 were first resolved separately at a resolution of 2.2 Å (IBC with bound IP3, [34]) and 1.8 Å (suppressor domain, [35]). Subsequent studies analyzed the crystal structure of the full ligand-binding domain, i.e. the suppressor domain and the IBC together, resolved in the presence and absence of bound IP3 at a resolution between 3.0 and 3.8 Å [36, 37]. These studies indicated that the N-terminus of IP3R1 consisted of two successive β-trefoil domains (β-TF) followed by an α-helical armadillo repeat domain. IP3 binds in a cleft between the second β-trefoil domain and the α-helical armadillo repeat, leading to a closure of the IP3-binding pocket and a conformational change of the domains involved [36,37,38]. Recently, Mikoshiba and co-workers succeeded to perform X-ray crystallography on the complete cytosolic part of the IP3R [39]. This study was performed using truncated IP3R1 proteins (IP3R2217 and IP3R1585) in which additional point mutations (resp. R937G and R922G) were incorporated in order to increase the quality of the obtained crystals. In addition to the three domains mentioned above (the two β-trefoil domains and the α-helical armadillo repeat domain), three large α-helical domains were described, i.e. HD1 (a.a. 605–1009), HD2 (a.a. 1026–1493) and HD3 (1593–2217) (Fig. 10.1b). Binding of IP3 induces a conformation change that is transmitted from the IBC through HD1 and HD3, whereby a short, 21 a.a.-long domain (a.a. 2195–2215) called the leaflet domain is essential for IP3R function.
In parallel with the analysis of the IP3R by X-ray crystallography, the structure of full-size IP3R1 was investigated by several groups by cryo-electron microscopy (cryo-EM), obtaining increasingly better resolution [40]. The structure of the IP3R1 at the highest resolution obtained by this method until now (4.7 Å) was published by Serysheva and co-workers and allowed modelling of the backbone topology of 2327 of the 2750 a.a [41]. As IP3R1 was purified in the absence of IP3 and as Ca2+ was depleted before vitrification, the obtained structure corresponds to the closed state of the channel (Fig. 10.2). In total, ten domains were identified: two contiguous β-trefoil domains (a.a. 1–436), followed by three armadillo solenoid folds (ARM1–ARM3, a.a. 437–2192) with an α-helical domain between ARM1 and 2, an intervening lateral domain (ILD, a.a. 2193–2272), the transmembrane region with six trans-membrane α-helices (TM1–6) (a.a. 2273–2600), a linker domain (LNK, a.a. 2601–2680) and the C-terminal domain containing an ~80 Å α-helix (a.a. 2681–2731) (Fig. 10.1c). The latter domains of the four subunits form together with the four TM6 helices (∼55 Å) a central core structure that is not found in other types of Ca2+ channels. The four transmembrane TM6 helices thereby line the Ca2+ conduction pathway and connect via their respective LNK domains with the cytosolic helices.
How binding of IP3 is coupled to channel opening is still under investigation. An interesting aspect of the IP3R structure thereby is the fact that either after mild trypsinisation of IP3R1 [42] or after heterologous expression of the various IP3R1 fragments corresponding to the domains obtained by trypsinisation [43], the resulting structure appeared both tetrameric and functional. This indicates that continuity of the polypeptide chain is not per se needed for signal transmission to the channel domain, although the resulting Ca2+ signals can differ, depending on the exact cleavage site and the IP3R isoform under consideration [44, 45].
Meanwhile, various models for the transmission of the IP3 signal to the channel region were proposed for IP3R1, including a direct coupling between the N-terminus and the C-terminus [41, 46,47,48] and a long-range coupling mediated by the central coupling domain [48], via intra- and/or inter-subunit interactions [41]. Mechanisms for the latter can involve β-TF1 ➔ ARM3 ➔ ILD [41] or IBC ➔ HD1 ➔ HD3 ➔ leaflet [39].
In addition to the structural studies on IP3R1 described above, the structure of human IP3R3 was recently analyzed at high resolution (between 3.3 and 4.3 Å) under various conditions. Its apo state was compared to the structures obtained at saturating IP3 and/or Ca2+ concentrations [49]. In the presence of IP3, five different conformational states were resolved, suggesting a dynamic transition between intermediate states eventually leading to channel opening. Ca2+ binding appeared to eliminate the inter-subunit interactions present in the apo and the IP3-bound states and provoke channel inhibition. Two Ca2+-binding sites were identified, one just upstream of ARM2 and one just upstream of ARM3, though their relative function cannot be inferred from structural data alone.
Although IP3R1 and IP3R3 are structurally quite similar, they are differentially activated and regulated (see Sect. 10.1). Additional work, including performing a high-resolution cryo-EM analysis of IP3-bound IP3R1 and the further investigation of the effect of Ca2+ and other IP3R modulators, including associated proteins, on IP3R structure will therefore be needed to fully unravel the underlying mechanism of activation and to understand the functional differences between the various IP3R isoforms.
10.3 Complexity of IP3R Activation and Regulation
Concerning the mechanisms of activation and regulation of the IP3R, progress has been made on several points recently.
10.3.1 IP3 Binding Stoichiometry
First, a long-standing question in the field concerned the number of IP3 molecules needed to evoke the opening of the IP3R/Ca2+-release channel. Some studies demonstrated a high cooperativity of IP3 binding to its receptor, and suggested that minimally 3 IP3 molecules should be bound to the IP3R to evoke Ca2+ release [50, 51]. In contrast herewith, co-expression of an IP3R apparently defective in IP3 binding (R265Q) and of a channel-dead IP3R mutant (D2550A) resulted in a partial IP3-induced Ca2+ release, suggesting that one IP3R subunit can gate another and that therefore not all subunits need to bind IP3 to form an active channel [52]. Moreover, these results fit with the most recent cryo-EM data discussed above (see Sect. 10.2.; [41]).
Recently, a comprehensive study by Yule and co-workers demonstrated in triple-knockout (TKO) cells, devoid of endogenous IP3R expression (DT-40 TKO and HEK TKO), that the activity of recomplemented IP3Rs depends on the occupation of the 4 IP3-binding sites by their ligand [53]. The strongest evidence for this was obtained by the expression of a concatenated IP3R1 containing 3 wild-type subunits and 1 mutant subunit. The mutant subunit contained a triple mutation (R265Q/K508Q/R511Q) in the ligand-binding domain precluding any IP3 binding, as previously demonstrated [54], while the R265Q single mutant still retained ~10% binding activity. Interestingly, the tetrameric IP3R containing only 1 defective IP3-binding site and expressed in cells fully devoid of endogenous IP3Rs was completely inactive in Ca2+ imaging experiments, unidirectional Ca2+ flux experiments and in patch-clamp electrophysiological experiments [53]. Similar experiments were performed for IP3R2, making use of its existing short splice isoform that lacks 33 a.a. in the suppressor domain rendering it non-functional [55]. These data strongly suggest that no opening of the IP3R can occur, unless each subunit has bound IP3. This characteristic would strongly limit the number of active IP3Rs and protect the cell against unwanted Ca2+ release in conditions in which the IP3 concentration is only slightly increased [50, 53]. However, in the case of IP3R mutations affecting IP3 binding / IP3R activity it may explain why they are detrimental, even in heterozygous conditions [10].
10.3.2 Physiological Relevance of IP3R Heterotetramer Formation
As already indicated above (see Sect. 10.1.), the high level of homology between the various IP3R isoforms allows not only for the formation of homotetramers but also for that of heterotetramers [57,58,59]. The frequency of heterotetramer occurrence is however not completely clear. A study in COS-7 cells indicated that kinetic constrains affect the formation of heterotetramers and that therefore the level of heterotetramers composed of overexpressed IP3R1 and of either endogenously expressed or overexpressed IP3R3 was lower than what could be expected from a purely binomial distribution [60]. In contrast herewith, by using isoform-specific IP3R antibodies for sequential depletion of the IP3Rs, it was shown that in pancreas, over 90% of IP3R3 is present in heterotetrameric complexes, generally with IP3R2 [61]. This is significant as pancreas is a tissue in which IP3R2 and IP3R3 together constitute over 80% of the total amount of IP3R [62, 63]. It is therefore meaningful to investigate whether the presence of IP3R heterotetramers will contribute in increasing the diversity of the IP3R Ca2+-release channels, as is generally assumed. However, due to the fact that most cells express or can express various types of homo- and heterotetrameric IP3Rs in unknown proportions, addressing this question is in most cell types not straightforward.
Overexpressing mutated IP3R1 and IP3R3 in COS-7 cells at least indicated that heterotetramers are functional [52]. The expression of concatenated dimeric IP3R1-IP3R2 (and IP3R2-IP3R1) in DT-40 TKO cells led to the formation of IP3R heterotetramers with a defined composition (2:2) that could be compared with homotetrameric IP3R1 or homotetrameric IP3R2 that were similarly expressed [61]. Investigation of their electrophysiological properties via nuclear patch-clamp recordings indicated that in the IP3R1-IP3R2 2:2 heterotetramers the properties of the IP3R2 dominated with respect to the induction of Ca2+ oscillations and their regulation by ATP [61]. A more recent study based on the same approach but now including combinations of all three IP3R isoforms, demonstrated that 2:2 heterotetrameric IP3Rs display an IP3 sensitivity that is intermediate to that of their respective homotetramers [64] indicating that heterotetramerization successfully increases IP3R diversity. In addition, the obtained results also demonstrate that IP3R2 properties with respect to both the induction of Ca2+ oscillations and the regulation by ATP also dominated in IP3R2-IP3R3 2:2 heterotetramers. In contrast, when a tetrameric IP3R containing 3 IP3R1 and 1 IP3R2 subunit was expressed, its properties were similar to that of a homotetrameric IP3R1 [64]. Taken together, these experiments indicate that IP3R heterotetramers increase the diversity of the IP3Rs with respect to Ca2+ release and that further studies are needed to fully understand how IP3R heterotetramers are regulated by other factors, including associated proteins.
10.3.3 Novel Crosstalk Mechanism Between cAMP and IICR
cAMP and Ca2+, the two most important intracellular messengers, have numerous crosstalks between them [65]. At the level of the IP3R, the most evident crosstalk is the sensitization of IP3R1 by cAMP-dependent protein kinase (PKA) [66], while a similar regulatory role is highly probable for IP3R2 but less likely for IP3R3 [15, 65].
A novel line of regulation was discovered some time ago when it was shown that cAMP can, independently from PKA or cAMP-activated exchange proteins, potentiate the IP3R [67,68,69]. In particular, it was shown in HEK cells that adenylate cyclase 6, which in those cells accounts for only a minor portion of the adenylate cyclase isoforms, is responsible for providing cAMP to a microdomain surrounding IP3R2, increasing its activity [69]. Such mechanism would form a specific signaling complex in which locally a very high concentration of cAMP could be reached, without affecting its global concentration [65]. Recent work provided further evidence concerning the importance of cAMP for IP3R functioning, showing that the presence of cAMP can uncover IP3Rs that were insensitive to IP3 alone [56]. Indeed, in HEK cells heterologously expressing the parathyroid hormone (PTH) receptor, it appears that PTH, via production of cAMP, evokes Ca2+ release after full depletion of the carbachol-sensitive Ca2+ stores. Although the identity of the Ca2+ stores could not yet be established, the obtained results are indicative that cAMP unmasks IP3Rs with a high affinity for IP3. This fits with the previous observation that IP3R2, the IP3R with the highest affinity for IP3 (reviewed in [19]), is regulated by cAMP [69]. The molecular mechanism on how cAMP interacts with the IP3R remains to be determined. At this moment no discrimination can be made between a low-affinity cAMP-binding site on the IP3R itself or a similar binding site on an associated protein [65]. The possibility that the IP3R-binding protein released by IP3 (IRBIT), related to protein S-adenosylhomocysteine-hydrolase, known to bind cAMP, is involved was however already excluded by knockdown and overexpression experiments [56].
10.4 Complexity of Protein-Protein Interactions Affecting the IP3R
In a comprehensive review published a few years ago, over 100 proteins that interact with the IP3R have been listed [14]. For that reason, we will limit ourselves in the present review to either newly discovered interacting proteins or proteins for which new information about their interaction recently became available.
10.4.1 Calmodulin (CaM) and Related Ca2+-Binding Proteins
CaM is the most ubiquitously expressed intracellular Ca2+ sensor. It is a relatively small protein (148 a.a.) with a typical dumbbell structure. A central, flexible linker region connects the globular N-terminal and C-terminal domains, each containing two Ca2+-binding EF-hand motifs with a classical helix-loop-helix structure. The Kd of CaM for Ca2+ ranges between 5 × 10−7 and 5 × 10−6 M, with the C-terminal Ca2+-binding sites having a three to five-fold higher affinity than the N-terminal ones [70]. CaM therefore displays the correct Ca2+ affinity to sense changes in intracellular Ca2+ concentrations and serve as Ca2+ sensor. While apo-CaM has a rather compact structure, Ca2+-CaM exposes in each domain a hydrophobic groove with acidic residues at its extremities that will allow interaction with their target [71]. A plethora of target proteins that are modulated by CaM exists, including various Ca2+-transporting proteins [72]. These various proteins contain CaM-binding sites that can be categorized into various types of motifs [73].
Although the interaction of CaM with the IP3R was already observed soon after the identification of the IP3R as IP3-sensitive Ca2+-release channel [74] its exact mechanism of action is still not completely elucidated. Moreover, there are a number of interesting features related to the binding of CaM to the IP3R: (i) the existence of multiple binding sites, (ii) the possibility for both Ca2+-CaM and apo-CaM to affect IP3R function and (iii) the use of some of the CaM-binding sites by other Ca2+-binding proteins. The aim of this paragraph therefore is to present a comprehensive view on the relation between CaM (and some related Ca2+-binding proteins) and the IP3R.
On IP3R1, three CaM-binding sites were described (Fig. 10.1). A high-affinity CaM-binding site (a.a. 1564–1585; Fig. 10.2a–b, indicated by the yellow arrows) was described in the central coupling domain [75], while a low-affinity one was found in the suppressor domain [76]. The latter site is discontinuous (a.a. 49–81 and a.a. 106–128; Fig. 10.2 , indicated in yellow) and can bind to both apo-CaM and Ca2+-CaM [77]. Finally, a third site was described on the S2(−) IP3R1 splice isoform in which a.a. 1693–1732 are removed [78, 79]. CaM binding to this newly formed site is inhibited by PKA-mediated phosphorylation, probably on Ser1589 [79].
CaM interaction with the two other IP3R isoforms was studied in less detail, but an IP3R2 construct overlapping with the CaM-binding site in the central coupling domain interacted with CaM, supporting the conservation of this site [75]. However, no direct interaction between CaM and IP3R3 could be measured [75, 80] though CaM can bind to IP3R1-IP3R3 heterotetramers [79].
Functional effects on the IP3R have been described for both apo-CaM and Ca2+-CaM. In fact, apo-CaM is equally potent in inhibiting IP3 binding to full-length IP3R1 as Ca2+-CaM [81]. In agreement with the absence of CaM binding to IP3R3, full-length IP3R3 remained insensitive to regulation by CaM [80]. In contrast, a Ca2+-independent inhibition of IP3 binding was observed for the isolated ligand-binding domain of IP3R1 [82] as well as for that of IP3R2 and IP3R3 [83].
Concerning IP3-induced Ca2+ release, the situation is somewhat more complex. Ca2+ release by IP3R1 is inhibited by CaM in a Ca2+-dependent way [84, 85] while similar results were subsequently found for IP3R2 and IP3R3 [76, 86]. However, linking these functional effects molecularly to a CaM-binding site appeared more difficult, not only because of the apparent absence of a Ca2+-dependent CaM-binding site on IP3R3 but also because the mutation W1577A that abolishes CaM binding to IP3R1 [75], does not abolish the CaM-mediated inhibition of IICR [87].
Furthermore, other results suggested that the relation between CaM and the IP3R was more complex than originally thought. A detailed analysis of the CaM-binding site located in the central coupling domain of IP3R1 provided evidence that it consisted of a high-affinity Ca2+-CaM and a lower affinity apo-CaM site [88]. Moreover, in the same study it was demonstrated that a CaM mutant deficient in Ca2+ binding (CaM1234) could inhibit IICR in a Ca2+-dependent way with the same potency as CaM. In a separate study, it was demonstrated that a myosin light chain kinase (MLCK)-derived peptide, which binds to CaM with high affinity, fully inhibited the IP3R [89]. This inhibition could be reversed by the addition of CaM but not of CaM1234 and the results were interpreted as evidence that endogenously bound CaM is needed for IP3R activity. A follow-up study by another group [90] however proposed that the MLCK peptide is not removing endogenous CaM but is interacting with an endogenous CaM-like domain on IP3R, thereby disrupting its interaction with a so-called 1–8-14 CaM-binding motif (a.a. 51–66) essential for IP3R activity [91].
Meanwhile, the interaction of apo-CaM with the suppressor domain was studied via NMR analysis [92]. This study brought forward two main pieces of evidence. First, it was shown that the binding of apo-CaM to the suppressor domain induced an important, general conformational change to the latter. These changes further increased in the presence of Ca2+. Secondly, analysis of the conformational change of CaM indicated that apo-CaM already binds with its C-lobe to the IP3R1 suppressor domain, and that only after addition of Ca2+ also the N-lobe interacts with the suppressor domain. These results can therefore explain the importance of the CaM-binding sites in the suppressor domain in spite of their difficult accessibility ( [92]; Fig. 10.2).
Finally, some Ca2+-binding proteins related to CaM (e.g. neuronal Ca2+-binding protein (CaBP) 1, calmyrin, also known as CIB1, and neuronal Ca2+ sensor-1 (NCS-1)) also regulate the IP3R. Similarly to CaM, these proteins contain 4 EF-hand motifs but in contrast with CaM, not all of them bind Ca2+. In CaBP1 and NCS-1 only 3 EF hands are functional (EF1, EF3, EF4 and EF2, EF3, EF4 resp.) and in calmyrin only 2 (EF3 and EF4). Moreover, some of the EF hands bind Mg2+ rather than Ca2+. Furthermore, those proteins are myristoylated. Although early results suggested that CaBP1 and calmyrin could, in the absence of IP3, activate the IP3R under some circumstances [93, 94], there is presently a large consensus that they, similarly to CaM, generally inhibit the IP3R [93, 95, 96].
CaBP1 was proposed to interact with the IP3R1 with a higher affinity than CaM itself [94, 96], while in contrast to CaM it does not affect the ryanodine receptor (RyR), another family of intracellular Ca2+-release channels. Additionally, the interaction with the IP3R would be subject to regulation by caseine kinase 2, an enzyme that can phosphorylate CaBP1 on S120 [96]. Similarly to CaM, CaBP1 binds in a Ca2+-independent way to the IP3R1 suppressor domain, but in contrast to CaM, only to the first of the two non-contiguous binding sites described for CaM (Fig. 10.1). However, CaM and CaBP1 similarly antagonized the thimerosal-stimulated interaction between the suppressor domain and the IBC of IP3R1, suggesting a common mechanism of action whereby they disrupt intramolecular interactions needed for channel activation [97]. More recent work confirmed the inhibitory effect of CaBP1 on IP3R1, while expanding the knowledge concerning the CaBP1 binding site. In particular, NMR analysis indicated that CaBP1 interacts with its C lobe with the suppressor domain of the IP3R and that even at saturating Ca2+ concentrations EF1 is bound to Mg2+, precluding a conformational change of the N lobe [98]. The same study demonstrated that Ca2+-bound CaBP1 bound with an ~10-fold higher affinity than Mg2+-bound CaBP1 and an at least 100-fold higher affinity than CaM itself. Functional analysis performed in DT-40 cells solely expressing IP3R1 demonstrated that CaBP1 stabilized the closed conformation of the channel, probably by clamping inter-subunit interactions [99]. The interaction of specific hydrophobic a.a. in the C lobe of CaBP1 (V101, L104, V162) that become more exposed in the presence of Ca2+ with hydrophobic a.a. in the IBC (L302, I364, L393) appeared hereby essential.
The action of NCS-1 on the IP3R forms a slightly different story. It co-immunoprecipitates with IP3R1 and IP3R2 in neuronal cells and in heart thereby stimulating IICR in a Ca2+-dependent way [100, 101]. Interestingly, paclitaxel by binding to NCS-1 increases its interaction with IP3R1 and so induces Ca2+ oscillations in various cell types [102, 103]. This Ca2+-signaling pathway was proposed to lead to calpain activation and to underlie the origin of paclitaxel-induced peripheral neuropathy [104]. However, the interaction site of NCS-1 on the IP3R, either direct or indirect, has not yet been identified.
Taken together these results confirm that Ca2+-binding proteins interact in a complex way with the IP3R and that the various Ca2+-binding proteins have distinct, though sometimes overlapping, roles. The functional effect of CaM has been studied in detail and it appears to inhibit the IP3R. The results described above support a view that the main action of CaM on the IP3R is at the level of the suppressor domain. Indeed, apo-CaM can via its C lobe bind to the suppressor domain of all three IP3R isoforms while a subsequent binding of the N lobe will depend on the Ca2+ concentration. The binding of CaM in that domain can disturb an intra-IP3R interaction needed for IP3R function and therefore inhibits IICR. This behavior can be particularly important in cells having high CaM expression levels, as for example Purkinje neurons that also demonstrate high levels of IP3R1. In that case, CaM was proposed to be responsible for suppressing basal IP3R activity [81]. Moreover, as the intracellular distribution of CaM can depend on intracellular Ca2+ dynamics, it was also hypothesized that it allows IP3R regulation is a non-uniform way [84]. Additionally, it should be emphasized that CaM can act on other Ca2+-transporting proteins in the cell, like the RyR [105], the plasma membrane Ca2+ ATPase [106] and various plasma membrane Ca2+ channels including voltage-operated Ca2+ channels and transient receptor potential channels [107, 108]. In all these cases CaM tends to inhibit Ca2+ influx into the cytosol (inhibition of IP3Rs, RyRs and plasma membrane Ca2+ channels) while promoting Ca2+ efflux out of the cell (stimulation of plasma membrane Ca2+ ATPase).
An IP3R-inhibiting behavior can similarly be expected for CaM-related Ca2+-binding proteins, though their interaction sites are not strictly identical to that of CaM. The binding site for NCS-1, which rather stimulates the IP3R, is even still unknown. In comparison to CaM, CaBP1 demonstrates a much higher affinity for the IP3R [99] and a higher specificity, as it does not affect the RyR [96]. In cells expressing CaBP1, the major control of IICR will therefore depend on the interaction of the IP3R with CaBP1, while RyR activity will depend on the presence and activation of CaM. Further work will be needed to completely unravel the exact role of these various proteins in the control of intracellular Ca2+ signaling. From the present results, it can already be expected that the relative role of the various Ca2+-binding proteins in the control of IICR will strongly depend on the exact cell type in consideration.
10.4.2 The Bcl-2-Protein Family
The B-cell lymphoma (Bcl)-2 protein family has been extensively studied as critical regulator of apoptosis [109]. This family consists of both anti- and pro-apoptotic members. The anti-apoptotic family members inhibit apoptosis in at least two different manners. First, at the mitochondria anti-apoptotic Bcl-2 proteins such as Bcl-2, Bcl-XL and Mcl-1, bind to the pro-apoptotic Bcl-2-family members thereby inhibiting the permeabilization of the outer mitochondrial membrane by Bax and Bak and subsequent release of cytochrome C [110, 111]. Second, the anti-apoptotic Bcl-2-family members also affect intracellular Ca2+ signaling. On the one hand they promote pro-survival Ca2+ oscillations while on the other hand they inhibit pro-apoptotic Ca2+ release from the ER that otherwise could lead to mitochondrial Ca2+ overload [112]. These combined actions mean that anti-apoptotic Bcl-2 proteins can, by modulating several protein families involved in intracellular Ca2+ signaling, both fine tune mitochondrial bio-energetics and inhibit Ca2+-mediated mitochondrial outer membrane permeabilization [113,114,115,116]. Both the interaction between Bcl-2-family members and their ability to regulate intracellular Ca2+ signaling is critically dependent on the presence of so-called Bcl-2 homology (BH) domains. Anti-apoptotic Bcl-2 proteins contain four of these domains (BH1, 2, 3 and 4) [111]. The BH1 to 3 domains together form a hydrophobic cleft that inactivates the pro-apoptotic Bcl-2-family members via interaction with their BH3 domain. For regulating intracellular Ca2+ signaling events, anti-apoptotic Bcl-2 proteins rely to a great extent, however not exclusively, on their BH4 domain. In this review we will focus on how IP3Rs are regulated by Bcl-2 proteins. For a more extensive revision of how Bcl-2-family members regulate the various members of the intracellular Ca2+ signaling machinery we would like to refer to our recent review on the subject [112].
The various IP3R isoforms are important targets for several anti-apoptotic Bcl-2-family members [112]. To complicate matters, multiple binding sites on the IP3R have been described for anti-apoptotic Bcl-2 proteins [117]. First, Bcl-2, Bcl-XL and Mcl-1 were shown to target the C-terminal part (a.a. 2512–2749) of IP3R1 (Fig. 10.2, indicated in green) thereby stimulating pro-survival Ca2+ oscillations [114, 115, 118]. Additionally, Bcl-2, and Bcl-XL with lesser affinity, also target the central coupling domain (a.a. 1389–1408 of IP3R1; Figs. 10.1 and 10.2, indicated in blue) of the IP3R where binding of these proteins inhibits pro-apoptotic Ca2+-release events [116, 118,119,120]. Finally, the zebrafish protein Nrz [121] and its mammalian homolog Bcl-2-like 10 [122] were shown to interact with the IBC and inhibit IICR.
The group of Kevin Foskett performed a more in-depth study into how the IP3R is regulated by Bcl-XL and proposed a mechanism unifying the regulation at the C-terminal and at the central coupling domain of the IP3R [123]. Two domains containing BH3-like structures (a.a. 2571–2606 and a.a. 2690–2732; Figs. 10.1 and 10.2 , indicated in dark green) were identified in the C-terminal part of the IP3R. When Bcl-XL is, via its hydrophobic cleft, bound to both BH3-like domains it sensitizes the IP3R to low concentrations of IP3, thereby stimulating Ca2+ oscillations. If Bcl-XL binds to only one of these BH3 like domains while also binding to the central coupling domain, it will inhibit IICR. Whether Bcl-XL occupies one or the two BH3-like domains at the C-terminus of the IP3R was proposed to be dependent on Bcl-XL levels and on the intensity of IP3R stimulation. Whether Bcl-2 operates in a similar manner is still unclear. As there is evidence that Bcl-2 shows a greater affinity than Bcl-XL for the inhibitory binding site in the central coupling domain it is likely that this site is the preferential target for Bcl-2 [118]. In addition, for Bcl-2 not its hydrophobic cleft but rather its transmembrane domain seems to play an important role for targeting and regulating the IP3R via both its C-terminus and the site located in the central coupling domain [124]. Based on the recent cryo-EM structure of IP3R1 [29, 41], this central site in the coupling domain resides in a relatively easily accessible area of IP3R1 (Fig. 10.2, indicated in blue). The C-terminal transmembrane domain of Bcl-2 may thus serve to concentrate the protein at the ER near the IP3R from where its N-terminal BH4 domain can more easily bind to the central coupling domain. In addition, sequestering Bcl-2 proteins at the ER membrane via their transmembrane domain may increase their ability to interact with the C-terminus of the IP3R (Fig. 10.2, indicated in green). As this C-terminal binding site seems to be located more at the inside of the IP3R1 tetramer one can expect a local high concentration of Bcl-2 proteins to be necessary for this interaction. Besides directly modulating IICR, Bcl-2 can serve as an anchor for targeting additional regulatory proteins to the IP3R. It was shown that Bcl-2 attracts dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and calcineurin to the IP3R thereby regulating the phosphorylation state of the latter and consequently its Ca2+-release properties [125]. Finally, recent data indicate also for Bcl-2 an additional interaction site in the ligand-binding domain [126] highlighting the complexity of the interaction of the anti-apoptotic Bcl-2-family members with the IP3R. Further research will be needed to unravel the precise function of each of these sites.
Another Bcl-2-family member that regulates the IP3R is the zebrafish protein Nrz. The latter was shown to bind via its BH4 domain to the IBC of zebrafish IP3R1, whereby E255 appeared essential for interaction (Fig. 10.1). Nrz prevents IP3 binding to the IP3R thereby inhibiting IICR [121]. Interestingly, although the Nrz BH4 domain is sufficient for interaction with the IP3R, inhibition of IICR required the BH4-BH3-BH1 domains. Furthermore, phosphorylation of Nrz abolished its interaction with the IP3R. Recently, Bcl-2-like 10, the human orthologue of Nrz, was shown, just like Nrz in zebrafish, to interact with the IBC, indicating a conserved function for this protein [122].
Besides anti-apoptotic Bcl-2-family members, also pro-apoptotic Bcl-2 proteins and other BH3 domain-containing proteins are known to target and regulate IP3Rs. For instance, Bok, a pro-apoptotic Bcl-2-family member, interacts with the IP3R (a.a. 1895–1903 of IP3R1; Figs. 10.1 and 10.2) [127]. This interaction protects IP3R1 and IP3R2 from proteolytic cleavage by caspase 3 that results in a Ca2+ leak that may contribute to mitochondrial Ca2+ overload and thus apoptosis [128, 129]. Subsequent work demonstrated that the majority of all cellular Bok is bound to the IP3R thereby stabilizing the Bok protein [130]. Unbound, newly synthesized Bok is rapidly turned over by the proteasome pathway. Both the association of mature Bok with the IP3R and the rapid degradation of newly synthesized Bok by the proteasome restrict the pro-apoptotic functions of Bok thus preventing cell death induction.
From the above it is clear that the IP3R is heavily regulated by both pro- and anti-apoptotic Bcl-2-family members. The occurrence of multiple binding sites for the same Bcl-2-family member further increases the complexity [112]. Furthermore, it should be stressed that the regulation of the IP3R by Bcl-2 proteins is conserved during evolution. This is illustrated by the ability of the zebrafish Nrz protein to regulate IICR via its BH4 domain [121] and is further validated by the observation that the BH4 domains of Bcl-2 derived from different vertebrates are able to inhibit IICR with similar efficiency [131]. The large number of both pro-and anti-apoptotic Bcl-2 proteins that regulate the IP3R, targeting it at multiple sites, suggests that throughout evolution regulating IICR became an important functional aspect of the Bcl-2-protein family.
Mcl-1, Bcl-2 and Bcl-XL all target the C-terminal region of the IP3R stimulating the occurrence of pro-survival Ca2+ oscillations and thus Ca2+ transfer to the mitochondria [114, 115, 118]. These Ca2+ transfers into the mitochondria are important for normal cell functioning [113] but are also involved in cancer development and could potentially form a novel therapeutic target [132]. Mitochondrial Ca2+ contributes to maintaining proper ATP production. When Ca2+ transfer into the mitochondria is inhibited, ATP levels decrease, activating autophagy. At the same time the cell cycle progression is halted [113, 133]. In cancer cells, decreased Ca2+ transfer into the mitochondria, consecutive loss of ATP and the start of autophagy is not accompanied by a stop in the cell cycle. Continuing the cell cycle without sufficient building blocks and ATP results in necrotic cell death [132]. Cancer cells are therefore reliant on proper Ca2+ transfer to the mitochondria to maintain mitochondrial function, including the production of ATP and metabolites necessary for completing the cell cycle. It is therefore common for cancer cells to upregulate one or several anti-apoptotic Bcl-2 proteins. By interacting with the C-terminus of the IP3R the Bcl-2 proteins may stimulate Ca2+ oscillations assuring proper mitochondrial Ca2+ uptake and an adequate mitochondrial metabolism. On the other hand, upregulation of Bcl-2 and/or Bcl-XL also protects the cells from excessive IP3R-mediated Ca2+ release by binding to the central regulatory site [116, 118,119,120] and prevents apoptosis, even in the presence of cell death inducers [109, 134]. In healthy cells a similar regulation of IICR by Bcl-2 proteins occurs. However, when cell death is induced in the latter, the amount of anti-apoptotic Bcl-2 proteins declines [134] potentially decreasing the level of their association with the IP3R. This alleviates the inhibitory actions on IICR allowing pro-death Ca2+ signals while also reducing the opportunities for the occurrence of pro-survival Ca2+ oscillations.
10.4.3 Beclin 1
Beclin 1 is a pro-autophagic BH3 domain-containing protein [135]. It interacts with various proteins involved in the regulation of autophagy, including Bcl-2 [136, 137]. The latter protein, by sequestering Beclin 1, prevents its pro-autophagic action. A first study presenting evidence that Beclin 1 also interacts with the IP3R showed an interaction between Beclin 1 and the IP3R that depended on Bcl-2 and which was disrupted by the IP3R inhibitor xestospongin B [138]. The release of Beclin 1 from the Bcl-2/IP3R complex resulted in the stimulation of autophagy which could be counteracted by overexpressing the IBC. This suggested that the IBC was able to sequester the xestospongin B-released Beclin 1 thus halting its pro-autophagic function. From subsequent work, it appeared that the role of Beclin 1 with respect to the IP3R was more complex [139]. Indeed, the binding of Beclin 1 to the ligand-binding domain was confirmed, though it appeared that in IP3R1 and to a lesser degree in IP3R3 the suppressor domain (a.a. 1–225) played a more prominent role in the interaction than the IBC. Interestingly, during starvation-induced autophagy Beclin 1 binding to the IP3R sensitized IICR that was shown to be essential for the autophagy process [139]. Using the F123A Beclin 1 mutant that does not interact with Bcl-2, it was shown that the sensitization of the IP3R by Beclin 1 was not due to counteracting the inhibitory effect of Bcl-2, although, in agreement with the previous study [138] it appeared that Beclin 1 binding to Bcl-2 may be needed to target the protein in proximity of the IP3R.
10.4.4 IRBIT
IRBIT regulates IICR by targeting the IP3R ligand-binding domain thereby competing with IP3. Moreover, this interaction is promoted by IRBIT phosphorylation [140]. Besides the IP3R, IRBIT binds to several other targets regulating a wide range of cellular processes [141]. How IRBIT determines which target to interact with and modulate was recently described [142]. First, various forms of IRBIT exist: IRBIT, the long-IRBIT homologue and its splice variants, which were shown to have distinct expression patterns. Besides this, the N-terminal region of the various members of the IRBIT-protein family showed distinct differences. These differences, obtained by N-terminal splicing, are important in maintaining protein stability and in determining which target to interact with.
Recently, it was shown that Bcl-2-like 10, which binds to a distinct site in the ligand-binding domain (see Sect. 10.4.2), functionally and structurally interferes with the action of IRBIT on the IP3R [122]. When both proteins are present, Bcl-2-like 10, via its BH4 domain, interacts with IRBIT, thereby mutually strengthening their interaction with the IP3R and decreasing IICR in an additive way. Upon dephosphorylation of IRBIT, both IRBIT and Bcl-2-like 10 are released from the IP3R, increasing pro-apoptotic Ca2+ transfer from the ER to the mitochondria. Interestingly, this study also showed that IRBIT is involved in regulating ER-mitochondrial contact sites as IRBIT knockout reduced the number of these contact sites [122].
10.4.5 Thymocyte-Expressed, Positive Selection-Associated 1 (TESPA1)
T-cell receptor (TCR) stimulation triggers a signaling cascade ultimately leading to the activation of PLC, production of IP3 and IICR important for T-cell maturation [143]. TESPA1, a protein involved in the development/selection of T cells [144], has been shown to regulate these Ca2+ signals. TESPA1 has a significant homology with KRAS-induced actin-interacting protein [147], a protein that was already shown to interact with and control the IP3R [145, 146]. TESPA1 similarly interacts with the various IP3R isoforms and it appeared that the full ligand-binding domain was needed for this interaction. However, at first no functional effect was described for this interaction [147]. Recently this topic was revisited and it was shown that TESPA1 recruits IP3R1 to the TCR where PLC signaling is initiated and IP3 produced [143]. In this way, TESPA1 promotes IP3R1 phosphorylation on Y353 by the tyrosine kinase Fyn, increasing the affinity of the IP3R for IP3. The combination of both these effects increases the efficiency by which Ca2+ signaling occurs after TCR stimulation, which is beneficial for T-cell selection and maturation [148]. Furthermore, in Jurkat cells TESPA1 interacts at the ER-mitochondria contact sites with GRP75 [149], a linker protein coupling IP3R with the mitochondrial VDAC1 channel favoring Ca2+ transfer from ER to mitochondria [150]. Consequently, TESPA1 knockout diminished the TCR-evoked Ca2+ transfers to both mitochondria and cytosol and confirm the important role for TESPA1 in these processes.
10.4.6 Pyruvate Kinase (PK) M2
PKs catalyze the last step of glycolysis and convert phosphoenolpyruvate to pyruvate resulting in the production of ATP. Many cancer cells preferentially upregulate glycolysis over oxidative phosphorylation suggesting a potential role for the PK family in cancer development. Four distinct PK isoforms exists, having each a distinct tissue expression pattern but PKM2 has the peculiarity to be expressed at an elevated level in most tumoral cells where it has a growth-promoting function. Moreover, although PKM1 and PKM2 are nearly identical, differing in only 22 a.a., they are regulated differently and have non-redundant functions [151]. Besides its metabolic functions, PKM2 is also involved in several non-metabolic functions. The latter encompass a nuclear role in transcriptional regulation, protein kinase activity towards various proteins in different cellular organelles, and even an extracellular function as PKM2 is also present in exosomes [152, 153]. It is therefore interesting that also a role for PKM2 at the ER was described since a direct interaction was found between PKM2 and the central coupling domain of the IP3R, inhibiting IICR in various cell types [154, 155]. Moreover, a recent study links the switch from oxidative phosphorylation to glycolysis in breast cancer cells with PKM2 methylation [156]. Methylated PKM2 promoted proliferation, migration and growth of various breast cancer cell lines. Strikingly, PKM2 methylation did not seem to alter its enzymatic activity but did however alter mitochondrial Ca2+ homeostasis by decreasing IP3R levels. Finally, co-immunoprecipitation experiments showed an interaction between methylated PKM2 and IP3R1 and IP3R3, though in this study it was not investigated whether the interaction was direct or indirect [156]. As PKM2 is in a variety of cancers considered as a good prognostic marker with a strong potential as therapeutic target [152] these new data, linking directly a metabolic enzyme with an intracellular Ca2+-release channel and ER-mitochondria Ca2+ transfer, provide new possibilities for therapeutic intervention.
10.4.7 BRCA-Associated Protein 1 (BAP1) and the F-Box Protein FBXL2
Prolonged stimulation of IP3Rs leads to a downregulation of the IP3R levels [157,158,159]. This downregulation is mainly due to IP3R ubiquitination followed by their degradation via the proteasomal pathway [31, 160]. Ubiquitination is therefore an important IP3R modification that may severely impact IICR signaling to for instance the mitochondria, thereby greatly affecting cell death and cell survival decisions. Recently a number of proto-oncogenes and tumor suppressors have been identified that critically control IP3R3 ubiquitination.
BAP1 is a tumor suppressor with deubiquitinase activity that is known to have important roles in regulating gene expression, DNA stability, replication, and repair and in maintaining chromosome stability [161,162,163,164]. Besides this, BAP1 was also shown to influence cellular metabolism, suggesting potential roles for BAP1 outside the nucleus [165, 166]. Heterozygous loss of BAP1 results in decreased mitochondrial respiration while increasing glycolysis [167, 168]. These cells produced a distinct metabolite signature, indicative for the occurrence of the Warburg effect that is supporting cells towards malignant transformation. Heterozygous loss of BAP1 leads to a decreased ER-mitochondria Ca2+ transfer and altered mitochondrial metabolism [167]. BAP1 regulates this Ca2+ transfer by interacting with the N-terminal part (a.a. 1–800) of IP3R3, a region which contains the complete ligand-binding domain and a small part of the central coupling domain. The deubiquitinase activity of BAP1 prevents degradation of IP3R3 by the proteasome. Loss of BAP1 consequently results in excessive reduction of IP3R3 levels thereby lowering mitochondrial Ca2+ uptake. This not only reduces the cell its responsiveness to Ca2+-induced cell death but also promotes glycolysis over oxidative phosphorylation, both important aspects of malignant cell transformation. The nuclear function of BAP1 with respect to maintaining DNA integrity [161,162,163,164] together with its extra-nuclear role in regulating cell metabolism and sensitivity to Ca2+-induced cell death [165,166,167,168] suggests that this protein may be an excellent target for cancer drug development.
F-box protein FBXL2 that forms a subunit of a ubiquitin ligase complex has the opposite effect of BAP1 on IP3R3. FBXL2 interacts with a.a. 545–566 of IP3R3, promoting its ubiquitination and its subsequent degradation. Reduced IP3R3 leads to a decreased transfer of Ca2+ to the mitochondria and a reduced sensitivity towards apoptosis, thus promoting tumor growth [169]. The phosphatase and tensin homolog (PTEN) tumor suppressor could inhibit this pro-tumorigenic effect of FBXL2. PTEN not only promotes apoptosis by inhibiting protein kinase B/Akt (PKB) [170,171,172] thereby counteracting PKB-mediated IP3R3 phosphorylation [173, 174] but also by directly binding to IP3R3 [169]. Binding of PTEN to IP3R3 displaces FBXL2 from its binding site, reducing IP3R3 ubiquitination, stabilizing IP3R3 levels, and thus increasing pro-apoptotic Ca2+ signaling to the mitochondria [169]. In accordance with the fact that the FBXL2-binding site is only partially conserved in IP3R1 and IP3R2, the stability of the two latter isoforms appeared to be affected neither by FBXL2 nor by PTEN.
In several tumors, PTEN function is impaired which results in accelerated IP3R3 degradation and impaired apoptosis induction. Treatment with drugs that stabilize IP3R levels may therefore also be of interest for cancer therapy in cases where PTEN is affected.
10.5 Conclusions
Intracellular Ca2+ signaling is involved in a plethora of cellular processes. The ubiquitously expressed IP3R Ca2+-release channels play an important role in the generation of these signals and serve as signaling hubs for several regulatory factors and proteins/protein complexes. Since the first identification of the IP3R [175], IP3R-interacting proteins and their modulating roles on Ca2+ signaling and (patho)physiological processes have been the subject of many studies and well over 100 interaction partners were reported [14], though for many of them it is unclear how they exactly interact with the IP3R and how they affect IP3R function. Moreover, for many regulatory proteins, multiple binding sites were described of which the relative importance is not directly apparent. The recent (and future) advances in the elucidation of the IP3R structure will pave the way for a better understanding how IP3R gating exactly occurs and how different cellular factors and regulatory proteins influence IICR. As several of these proteins affect life and death decisions and/or play important roles in tumor development, the exact knowledge of their interaction site and their action of the IP3R may lead to the development of new therapies for e.g. cancer treatment.
Abbreviations
- a.a.:
-
amino acids
- BAP1:
-
BRCA-associated protein 1
- Bcl:
-
B-cell lymphoma
- BH:
-
Bcl-2 homology
- CaBP:
-
neuronal Ca2+-binding protein
- CaM:
-
calmodulin
- CaM1234:
-
calmodulin fully deficient in Ca2+ binding
- cryo-EM:
-
cryo-electron microscopy
- DARPP-32:
-
dopamine- and cAMP-regulated phosphoprotein of 32 kDa
- ER:
-
endoplasmic reticulum
- IBC:
-
IP3-binding core
- IICR:
-
IP3-induced Ca2+ release
- IP3 :
-
inositol 1,4,5-trisphosphate
- IP3R:
-
IP3 receptor
- IRBIT:
-
IP3R-binding protein released by IP3
- MLCK:
-
myosin light chain kinase
- NCS-1:
-
neuronal Ca2+ sensor-1
- PK:
-
pyruvate kinase
- PKA:
-
cAMP-dependent protein kinase
- PKB:
-
protein kinase B/Akt
- PLC:
-
phospholipase C
- PTEN:
-
phosphatase and tensin homolog
- RyR:
-
ryanodine receptor
- TCR:
-
T-cell receptor
- TESPA1:
-
thymocyte-expressed, positive selection-associated 1
- TIRF:
-
total internal reflection fluorescence
- TKO:
-
triple-knockout
References
Vermassen E, Parys JB, Mauger JP (2004) Subcellular distribution of the inositol 1,4,5-trisphosphate receptors: functional relevance and molecular determinants. Biol Cell 96:3–17
Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529
Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21
Berridge MJ (2016) The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol Rev 96:1261–1296
Tada M, Nishizawa M, Onodera O (2016) Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias. Neurochem Int 94:1–8
Egorova PA, Bezprozvanny IB (2018) Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J 285:3547–3565
Hisatsune C, Mikoshiba K (2017) IP3 receptor mutations and brain diseases in human and rodents. J Neurochem 141:790–807
Hisatsune C, Hamada K, Mikoshiba K (2018) Ca2+ signaling and spinocerebellar ataxia. Biochim Biophys Acta 1865:1733–1744
Kerkhofs M, Seitaj B, Ivanova H, Monaco G, Bultynck G, Parys JB (2018) Pathophysiological consequences of isoform-specific IP3 receptor mutations. Biochim Biophys Acta 1865: 1707–1717
Terry LE, Alzayady KJ, Furati E, Yule DI (2018) Inositol 1,4,5-trisphosphate receptor mutations associated with human disease. Messenger 6:29–44
Fedorenko OA, Popugaeva E, Enomoto M, Stathopulos PB, Ikura M, Bezprozvanny I (2014) Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39–48
Foskett JK, White C, Cheung KH, Mak DO (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87:593–658
Parys JB, De Smedt H (2012) Inositol 1,4,5-trisphosphate and its receptors. Adv Exp Med Biol 740:255–279
Prole DL, Taylor CW (2016) Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs. J Physiol 594:2849–2866
Vanderheyden V, Devogelaere B, Missiaen L, De Smedt H, Bultynck G, Parys JB (2009) Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta 1793:959–970
Ivanova H, Vervliet T, Missiaen L, Parys JB, De Smedt H, Bultynck G (2014) Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival. Biochim Biophys Acta 1843:2164–2183
Patel S, Joseph SK, Thomas AP (1999) Molecular properties of inositol 1,4,5-trisphosphate receptors. Cell Calcium 25:247–264
Taylor CW, Genazzani AA, Morris SA (1999) Expression of inositol trisphosphate receptors. Cell Calcium 26:237–251
Vervloessem T, Yule DI, Bultynck G, Parys JB (2015) The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel. Biochim Biophys Acta 1853:1992–2005
Gutierrez T, Simmen T (2018) Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. Cell Calcium 70:64–75
La Rovere RM, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca2+ signaling and Ca2+ microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60: 74–87
Marchi S, Bittremieux M, Missiroli S, Morganti C, Patergnani S, Sbano L et al (2017) Endoplasmic reticulum-mitochondria communication through Ca2+ signaling: the importance of mitochondria-associated membranes (MAMs). Adv Exp Med Biol 997:49–67
Marchi S, Patergnani S, Missiroli S, Morciano G, Rimessi A, Wieckowski MR et al (2018) Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium 69:62–72
Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41:1035–1049
Ando H, Kawaai K, Bonneau B, Mikoshiba K (2018) Remodeling of Ca2+ signaling in cancer: regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors. Adv Biol Regul 68:64–76
Garcia MI, Boehning D (2017) Cardiac inositol 1,4,5-trisphosphate receptors. Biochim Biophys Acta 1864:907–914
Kania E, Roest G, Vervliet T, Parys JB, Bultynck G (2017) IP3 receptor-mediated calcium signaling and its role in autophagy in cancer. Front Oncol 7:140
Roest G, La Rovere RM, Bultynck G, Parys JB (2017) IP3 receptor properties and function at membrane contact sites. Adv Exp Med Biol 981:149–178
Serysheva II, Baker MR, Fan G (2017) Structural insights into IP3R function. Adv Exp Med Biol 981:121–147
Wang L, Alzayady KJ, Yule DI (2016) Proteolytic fragmentation of inositol 1,4,5-trisphosphate receptors: a novel mechanism regulating channel activity? J Physiol 594: 2867–2876
Wright FA, Wojcikiewicz RJ (2016) Chapter 4 – inositol 1,4,5-trisphosphate receptor ubiquitination. Prog Mol Biol Transl Sci 141:141–159
Eid AH, El-Yazbi AF, Zouein F, Arredouani A, Ouhtit A, Rahman MM et al (2018) Inositol 1,4,5-trisphosphate receptors in hypertension. Front Physiol 9:1018
Uchida K, Miyauchi H, Furuichi T, Michikawa T, Mikoshiba K (2003) Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 278:16551–16560
Bosanac I, Alattia JR, Mal TK, Chan J, Talarico S, Tong FK et al (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420: 696–700
Bosanac I, Yamazaki H, Matsu-Ura T, Michikawa T, Mikoshiba K, Ikura M (2005) Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor. Mol Cell 17:193–203
Lin CC, Baek K, Lu Z (2011) Apo and InsP3-bound crystal structures of the ligand-binding domain of an InsP3 receptor. Nat Struct Mol Biol 18:1172–1174
Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA et al (2012) Structural and functional conservation of key domains in InsP3 and ryanodine receptors. Nature 483:108–112
Bosanac I, Michikawa T, Mikoshiba K, Ikura M (2004) Structural insights into the regulatory mechanism of IP3 receptor. Biochim Biophys Acta 1742:89–102
Hamada K, Miyatake H, Terauchi A, Mikoshiba K (2017) IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography. Proc Natl Acad Sci USA 114:4661–4666
Taylor CW, da Fonseca PC, Morris EP (2004) IP3 receptors: the search for structure. Trends Biochem Sci 29:210–219
Fan G, Baker ML, Wang Z, Baker MR, Sinyagovskiy PA, Chiu W et al (2015) Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature 527:336–341
Yoshikawa F, Iwasaki H, Michikawa T, Furuichi T, Mikoshiba K (1999) Trypsinized cerebellar inositol 1,4,5-trisphosphate receptor. Structural and functional coupling of cleaved ligand binding and channel domains. J Biol Chem 274:316–327
Wang L, Wagner LE 2nd, Alzayady KJ, Yule DI (2017) Region-specific proteolysis differentially regulates type 1 inositol 1,4,5-trisphosphate receptor activity. J Biol Chem 292:11714–11726
Wang L, Yule DI (2018) Differential regulation of ion channels function by proteolysis. Biochim Biophys Acta 1865:1698–1706
Wang L, Wagner LE 2nd, Alzayady KJ, Yule DI (2018) Region-specific proteolysis differentially modulates type 2 and type 3 inositol 1,4,5-trisphosphate receptor activity in models of acute pancreatitis. J Biol Chem 293:13112–13124
Chan J, Yamazaki H, Ishiyama N, Seo MD, Mal TK, Michikawa T et al (2010) Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating. J Biol Chem 285:36092–36099
Schug ZT, Joseph SK (2006) The role of the S4-S5 linker and C-terminal tail in inositol 1,4,5-trisphosphate receptor function. J Biol Chem 281:24431–24440
Yamazaki H, Chan J, Ikura M, Michikawa T, Mikoshiba K (2010) Tyr-167/Trp-168 in type 1/3 inositol 1,4,5-trisphosphate receptor mediates functional coupling between ligand binding and channel opening. J Biol Chem 285:36081–36091
Paknejad N, Hite RK (2018) Structural basis for the regulation of inositol trisphosphate receptors by Ca2+ and IP3. Nat Struct Mol Biol 25:660–668
Marchant JS, Taylor CW (1997) Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity. Curr Biol 7:510–518
Meyer T, Holowka D, Stryer L (1988) Highly cooperative opening of calcium channels by inositol 1,4,5-trisphosphate. Science 240:653–656
Boehning D, Joseph SK (2000) Direct association of ligand-binding and pore domains in homo- and heterotetrameric inositol 1,4,5-trisphosphate receptors. EMBO J 19:5450–5459
Alzayady KJ, Wang L, Chandrasekhar R, Wagner LE 2nd, Van Petegem F, Yule DI (2016) Defining the stoichiometry of inositol 1,4,5-trisphosphate binding required to initiate Ca2+ release. Sci Signal 9:ra35
Yoshikawa F, Morita M, Monkawa T, Michikawa T, Furuichi T, Mikoshiba K (1996) Mutational analysis of the ligand binding site of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 271:18277–18284
Iwai M, Tateishi Y, Hattori M, Mizutani A, Nakamura T, Futatsugi A et al (2005) 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 Biol Chem 280:10305–10317
Konieczny V, Tovey SC, Mataragka S, Prole DL, Taylor CW (2017) Cyclic AMP recruits a discrete intracellular Ca2+ store by unmasking hypersensitive IP3 receptors. Cell Rep 18: 711–722
Joseph SK, Lin C, Pierson S, Thomas AP, Maranto AR (1995) Heteroligomers of type-I and type-III inositol trisphosphate receptors in WB rat liver epithelial cells. J Biol Chem 270:23310–23316
Monkawa T, Miyawaki A, Sugiyama T, Yoneshima H, Yamamoto-Hino M, Furuichi T et al (1995) Heterotetrameric complex formation of inositol 1,4,5-trisphosphate receptor subunits. J Biol Chem 270:14700–14704
Wojcikiewicz RJ, He Y (1995) Type I, II and III inositol 1,4,5-trisphosphate receptor co-immunoprecipitation as evidence for the existence of heterotetrameric receptor complexes. Biochem Biophys Res Commun 213:334–341
Joseph SK, Bokkala S, Boehning D, Zeigler S (2000) Factors determining the composition of inositol trisphosphate receptor hetero-oligomers expressed in COS cells. J Biol Chem 275:16084–16090
Alzayady KJ, Wagner LE 2nd, Chandrasekhar R, Monteagudo A, Godiska R, Tall GG et al (2013) Functional inositol 1,4,5-trisphosphate receptors assembled from concatenated homo- and heteromeric subunits. J Biol Chem 288:29772–29784
De Smedt H, Missiaen L, Parys JB, Henning RH, Sienaert I, Vanlingen S et al (1997) Isoform diversity of the inositol trisphosphate receptor in cell types of mouse origin. Biochem J 322:575–583
Wojcikiewicz RJ (1995) Type I, II, and III inositol 1,4,5-trisphosphate receptors are unequally susceptible to down-regulation and are expressed in markedly different proportions in different cell types. J Biol Chem 270:11678–11683
Chandrasekhar R, Alzayady KJ, Wagner LE 2nd, Yule DI (2016) Unique regulatory properties of heterotetrameric inositol 1,4,5-trisphosphate receptors revealed by studying concatenated receptor constructs. J Biol Chem 291:4846–4860
Taylor CW (2017) Regulation of IP3 receptors by cyclic AMP. Cell Calcium 63:48–52
Wagner LE 2nd, Joseph SK, Yule DI (2008) Regulation of single inositol 1,4,5-trisphosphate receptor channel activity by protein kinase A phosphorylation. J Physiol 586:3577–3596
Meena A, Tovey SC, Taylor CW (2015) Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions. J Cell Sci 128:408–420
Tovey SC, Dedos SG, Rahman T, Taylor EJ, Pantazaka E, Taylor CW (2010) Regulation of inositol 1,4,5-trisphosphate receptors by cAMP independent of cAMP-dependent protein kinase. J Biol Chem 285:12979–12989
Tovey SC, Dedos SG, Taylor EJ, Church JE, Taylor CW (2008) Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP. J Cell Biol 183:297–311
Chin D, Means AR (2000) Calmodulin: a prototypical calcium sensor. Trends Cell Biol 10:322–328
Villarroel A, Taglialatela M, Bernardo-Seisdedos G, Alaimo A, Agirre J, Alberdi A et al (2014) The ever changing moods of calmodulin: how structural plasticity entails transductional adaptability. J Mol Biol 426:2717–2735
Tidow H, Nissen P (2013) Structural diversity of calmodulin binding to its target sites. FEBS J 280:5551–5565
Yap KL, Kim J, Truong K, Sherman M, Yuan T, Ikura M (2000) Calmodulin target database. J Struct Funct Genom 1:8–14
Maeda N, Kawasaki T, Nakade S, Yokota N, Taguchi T, Kasai M et al (1991) Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum. J Biol Chem 266:1109–1116
Yamada M, Miyawaki A, Saito K, Nakajima T, Yamamoto-Hino M, Ryo Y et al (1995) The calmodulin-binding domain in the mouse type 1 inositol 1,4,5-trisphosphate receptor. Biochem J 308:83–88
Adkins CE, Morris SA, De Smedt H, Sienaert I, Török K, Taylor CW (2000) Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, −2 and −3 inositol trisphosphate receptors. Biochem J 345:357–363
Sienaert I, Nadif Kasri N, Vanlingen S, Parys JB, Callewaert G, Missiaen L et al (2002) Localization and function of a calmodulin-apocalmodulin-binding domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor. Biochem J 365:269–277
Islam MO, Yoshida Y, Koga T, Kojima M, Kangawa K, Imai S (1996) Isolation and characterization of vascular smooth muscle inositol 1,4,5-trisphosphate receptor. Biochem J 316:295–302
Lin C, Widjaja J, Joseph SK (2000) The interaction of calmodulin with alternatively spliced isoforms of the type-I inositol trisphosphate receptor. J Biol Chem 275:2305–2311
Cardy TJ, Taylor CW (1998) A novel role for calmodulin: Ca2+-independent inhibition of type-1 inositol trisphosphate receptors. Biochem J 334:447–455
Patel S, Morris SA, Adkins CE, O'Beirne G, Taylor CW (1997) Ca2+-independent inhibition of inositol trisphosphate receptors by calmodulin: redistribution of calmodulin as a possible means of regulating Ca2+ mobilization. Proc Natl Acad Sci U S A 94:11627–11632
Sipma H, De Smet P, Sienaert I, Vanlingen S, Missiaen L, Parys JB et al (1999) Modulation of inositol 1,4,5-trisphosphate binding to the recombinant ligand-binding site of the type-1 inositol 1,4, 5-trisphosphate receptor by Ca2+ and calmodulin. J Biol Chem 274: 12157–12162
Vanlingen S, Sipma H, De Smet P, Callewaert G, Missiaen L, De Smedt H et al (2000) Ca2+ and calmodulin differentially modulate myo-inositol 1,4, 5-trisphosphate (IP3)-binding to the recombinant ligand-binding domains of the various IP3 receptor isoforms. Biochem J 346:275–280
Michikawa T, Hirota J, Kawano S, Hiraoka M, Yamada M, Furuichi T et al (1999) Calmodulin mediates calcium-dependent inactivation of the cerebellar type 1 inositol 1,4,5-trisphosphate receptor. Neuron 23:799–808
Missiaen L, Parys JB, Weidema AF, Sipma H, Vanlingen S, De Smet P et al (1999) The bell-shaped Ca2+ dependence of the inositol 1,4, 5-trisphosphate-induced Ca2+ release is modulated by Ca2+/calmodulin. J Biol Chem 274:13748–13751
Missiaen L, DeSmedt H, Bultynck G, Vanlingen S, Desmet P, Callewaert G et al (2000) Calmodulin increases the sensitivity of type 3 inositol-1,4, 5-trisphosphate receptors to Ca2+ inhibition in human bronchial mucosal cells. Mol Pharmacol 57:564–567
Nosyreva E, Miyakawa T, Wang Z, Glouchankova L, Mizushima A, Iino M et al (2002) The high-affinity calcium-calmodulin-binding site does not play a role in the modulation of type 1 inositol 1,4,5-trisphosphate receptor function by calcium and calmodulin. Biochem J 365:659–367
Kasri NN, Bultynck G, Smyth J, Szlufcik K, Parys JB, Callewaert G et al (2004) The N-terminal Ca2+-independent calmodulin-binding site on the inositol 1,4,5-trisphosphate receptor is responsible for calmodulin inhibition, even though this inhibition requires Ca2+. Mol Pharmacol 66:276–284
Kasri NN, Török K, Galione A, Garnham C, Callewaert G, Missiaen L et al (2006) Endogenously bound calmodulin is essential for the function of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 281:8332–8338
Sun Y, Taylor CW (2008) A calmodulin antagonist reveals a calmodulin-independent interdomain interaction essential for activation of inositol 1,4,5-trisphosphate receptors. Biochem J 416:243–253
Sun Y, Rossi AM, Rahman T, Taylor CW (2013) Activation of IP3 receptors requires an endogenous 1-8-14 calmodulin-binding motif. Biochem J 449:39–49
Kang S, Kwon H, Wen H, Song Y, Frueh D, Ahn HC et al (2011) Global dynamic conformational changes in the suppressor domain of IP3 receptor by stepwise binding of the two lobes of calmodulin. FASEB J 25:840–850
White C, Yang J, Monteiro MJ, Foskett JK (2006) CIB1, a ubiquitously expressed Ca2+-binding protein ligand of the InsP3 receptor Ca2+ release channel. J Biol Chem 281: 20825–20833
Yang J, McBride S, Mak DO, Vardi N, Palczewski K, Haeseleer F et al (2002) Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels. Proc Natl Acad Sci U S A 99:7711–7716
Haynes LP, Tepikin AV, Burgoyne RD (2004) Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling. J Biol Chem 279:547–555
Kasri NN, Holmes AM, Bultynck G, Parys JB, Bootman MD, Rietdorf K et al (2004) Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins. EMBO J 23: 312–321
Bultynck G, Szlufcik K, Kasri NN, Assefa Z, Callewaert G, Missiaen L et al (2004) Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction. Biochem J 381:87–96
Li C, Chan J, Haeseleer F, Mikoshiba K, Palczewski K, Ikura M et al (2009) Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1. J Biol Chem 284:2472–2481
Li C, Enomoto M, Rossi AM, Seo MD, Rahman T, Stathopulos PB et al (2013) CaBP1, a neuronal Ca2+ sensor protein, inhibits inositol trisphosphate receptors by clamping intersubunit interactions. Proc Natl Acad Sci U S A 110:8507–8512
Nakamura TY, Jeromin A, Mikoshiba K, Wakabayashi S (2011) Neuronal calcium sensor-1 promotes immature heart function and hypertrophy by enhancing Ca2+ signals. Circ Res 109:512–523
Schlecker C, Boehmerle W, Jeromin A, DeGray B, Varshney A, Sharma Y et al (2006) Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium. J Clin Invest 116:1668–1674
Zhang K, Heidrich FM, DeGray B, Boehmerle W, Ehrlich BE (2010) Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R. J Mol Cell Cardiol 49:829–835
Boehmerle W, Splittgerber U, Lazarus MB, McKenzie KM, Johnston DG, Austin DJ et al (2006) Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism. Proc Natl Acad Sci USA 103: 18356–18361
Boeckel GR, Ehrlich BE (2018) NCS-1 is a regulator of calcium signaling in health and disease. Biochim Biophys Acta 1865:1660–1667
Meissner G (2017) The structural basis of ryanodine receptor ion channel function. J Gen Physiol 149:1065–1089
Brini M, Cali T, Ottolini D, Carafoli E (2013) The plasma membrane calcium pump in health and disease. FEBS J 280:5385–5397
Hasan R, Zhang X (2018) Ca2+ regulation of TRP ion channels. Int J Mol Sci 19:1256
Saimi Y, Kung C (2002) Calmodulin as an ion channel subunit. Annu Rev Physiol 64: 289–311
Letai AG (2008) Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer 8:121–132
Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122:437–441
Davids MS, Letai A (2012) Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol 30:3127–3135
Vervliet T, Parys JB, Bultynck G (2016) Bcl-2 proteins and calcium signaling: complexity beneath the surface. Oncogene 35:5079–5092
Cárdenas C, Miller RA, Smith I, Bui T, Molgó J, Müller M et al (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142: 270–283
Eckenrode EF, Yang J, Velmurugan GV, Foskett JK, White C (2010) Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem 285:13678–13684
White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB et al (2005) The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat Cell Biol 7: 1021–1028
Rong YP, Bultynck G, Aromolaran AS, Zhong F, Parys JB, De Smedt H et al (2009) The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106:14397–14402
Parys JB (2014) The IP3 receptor as a hub for Bcl-2 family proteins in cell death control and beyond. Sci Signal 7:pe4
Monaco G, Beckers M, Ivanova H, Missiaen L, Parys JB, De Smedt H et al (2012) Profiling of the Bcl-2/Bcl-XL-binding sites on type 1 IP3 receptor. Biochem Biophys Res Commun 428:31–35
Monaco G, Decrock E, Akl H, Ponsaerts R, Vervliet T, Luyten T et al (2012) Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-xl. Cell Death Differ 19:295–309
Rong YP, Aromolaran AS, Bultynck G, Zhong F, Li X, McColl K et al (2008) Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2’s inhibition of apoptotic calcium signals. Mol Cell 31:255–265
Bonneau B, Nougarede A, Prudent J, Popgeorgiev N, Peyrieras N, Rimokh R et al (2014) The Bcl-2 homolog Nrz inhibits binding of IP3 to its receptor to control calcium signaling during zebrafish epiboly. Sci Signal 7:ra14
Bonneau B, Ando H, Kawaai K, Hirose M, Takahashi-Iwanaga H, Mikoshiba K (2016) IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact. elife 5:e19896
Yang J, Vais H, Gu W, Foskett JK (2016) Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability. Proc Natl Acad Sci USA 113:E1953–E1962
Ivanova H, Ritaine A, Wagner L, Luyten T, Shapovalov G, Welkenhuyzen K et al (2016) The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition. Oncotarget 7:55704–55720
Chang MJ, Zhong F, Lavik AR, Parys JB, Berridge MJ, Distelhorst CW (2014) Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival. Proc Natl Acad Sci U S A 111:1186–1191
Ivanova H, Wagner LE, 2nd, Tanimura A, Vandermarliere E, Luyten T, Welkenhuyzen K et al (2019) Bcl-2 and IP3 compete for the ligand-binding domain of IP3Rs modulating Ca2+ signaling output. Cell Mol Life Sci. In press
Schulman JJ, Wright FA, Kaufmann T, Wojcikiewicz RJ (2013) The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage. J Biol Chem 288:25340–25349
Assefa Z, Bultynck G, Szlufcik K, Nadif Kasri N, Vermassen E, Goris J et al (2004) Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis. J Biol Chem 279:43227–43236
Hirota J, Furuichi T, Mikoshiba K (1999) Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner. J Biol Chem 274:34433–34437
Schulman JJ, Wright FA, Han X, Zluhan EJ, Szczesniak LM, Wojcikiewicz RJ (2016) The stability and expression level of Bok are governed by binding to inositol 1,4,5-trisphosphate receptors. J Biol Chem 291:11820–11828
Ivanova H, Luyten T, Decrock E, Vervliet T, Leybaert L, Parys JB et al (2017) The BH4 domain of Bcl-2 orthologues from different classes of vertebrates can act as an evolutionary conserved inhibitor of IP3 receptor channels. Cell Calcium 62:41–66
Cárdenas C, Müller M, McNeal A, Lovy A, Jana F, Bustos G et al (2016) Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from endoplasmic reticulum to mitochondria. Cell Rep 14:2313–2324
Finkel T, Hwang PM (2009) The Krebs cycle meets the cell cycle: mitochondria and the G1-S transition. Proc Natl Acad Sci USA 106:11825–11826
Distelhorst CW (2018) Targeting Bcl-2-IP3 receptor interaction to treat cancer: a novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones. Biochim Biophys Acta 1865:1795–1804
He C, Levine B (2010) The Beclin 1 interactome. Curr Opin Cell Biol 22:140–149
Decuypere JP, Parys JB, Bultynck G (2012) Regulation of the autophagic Bcl-2/Beclin 1 interaction. Cell 1:284–312
Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S et al (2007) Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 3:561–568
Vicencio JM, Ortiz C, Criollo A, Jones AW, Kepp O, Galluzzi L et al (2009) The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 16:1006–1017
Decuypere JP, Welkenhuyzen K, Luyten T, Ponsaerts R, Dewaele M, Molgo J et al (2011) Ins(1,4,5)P3 receptor-mediated Ca2+ signaling and autophagy induction are interrelated. Autophagy 7:1472–1489
Ando H, Mizutani A, Matsu-ura T, Mikoshiba K (2003) IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor. J Biol Chem 278:10602–10612
Ando H, Kawaai K, Mikoshiba K (2014) IRBIT: a regulator of ion channels and ion transporters. Biochim Biophys Acta 1843:2195–2204
Kawaai K, Ando H, Satoh N, Yamada H, Ogawa N, Hirose M et al (2017) Splicing variation of long-IRBIT determines the target selectivity of IRBIT family proteins. Proc Natl Acad Sci USA 114:3921–3926
Liang J, Lyu J, Zhao M, Li D, Zheng M, Fang Y et al (2017) Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. Nat Commun 8:15732
Wang D, Zheng M, Lei L, Ji J, Yao Y, Qiu Y et al (2012) Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat Immunol 13:560–568
Dingli F, Parys JB, Loew D, Saule S, Mery L (2012) Vimentin and the K-Ras-induced actin-binding protein control inositol-(1,4,5)-trisphosphate receptor redistribution during MDCK cell differentiation. J Cell Sci 125:5428–5440
Fujimoto T, Machida T, Tanaka Y, Tsunoda T, Doi K, Ota T et al (2011) KRAS-induced actin-interacting protein is required for the proper localization of inositol 1,4,5-trisphosphate receptor in the epithelial cells. Biochem Biophys Res Commun 407:438–443
Matsuzaki H, Fujimoto T, Ota T, Ogawa M, Tsunoda T, Doi K et al (2012) Tespa1 is a novel inositol 1,4,5-trisphosphate receptor binding protein in T and B lymphocytes. FEBS Open Bio 2:255–259
Malissen B, Gregoire C, Malissen M, Roncagalli R (2014) Integrative biology of T cell activation. Nat Immunol 15:790–797
Matsuzaki H, Fujimoto T, Tanaka M, Shirasawa S (2013) Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux. Biochem Biophys Res Commun 433:322–326
Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D et al (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911
Dayton TL, Jacks T, Vander Heiden MG (2016) PKM2, cancer metabolism, and the road ahead. EMBO Rep 17:1721–1730
Hsu MC, Hung WC (2018) Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling. Mol Cancer 17:35
Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L et al (2016) PKM2 and cancer: the function of PKM2 beyond glycolysis. Oncol Lett 11:1980–1986
Lavik AR (2016) The role of inositol 1,4,5-trisphosphate receptor-interacting proteins in regulating inositol 1,4,5-trisphosphate receptor-dependent calcium signals and cell survival. PhD thesis, Case Western Reserve University, USA. https://etd.ohiolink.edu/!etd.send_file?accession=case1448532307&disposition=inline
Lavik A, Harr M, Kerkhofs M, Parys JB, Bultynck G, Bird G et al (2018) IP3Rs recruit the glycolytic enzyme PKM2 to the ER, promoting Ca2+ homeostasis and survival in hematologic malignancies. In: Abstract 66, 15th International meeting of the European Calcium Society. Hamburg, Germany
Liu F, Ma F, Wang Y, Hao L, Zeng H, Jia C et al (2017) PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis. Nat Cell Biol 19:1358–1370
Sipma H, Deelman L, Smedt HD, Missiaen L, Parys JB, Vanlingen S et al (1998) Agonist-induced down-regulation of type 1 and type 3 inositol 1,4,5-trisphosphate receptors in A7r5 and DDT1 MF-2 smooth muscle cells. Cell Calcium 23:11–21
Wojcikiewicz RJ, Furuichi T, Nakade S, Mikoshiba K, Nahorski SR (1994) Muscarinic receptor activation down-regulates the type I inositol 1,4,5-trisphosphate receptor by accelerating its degradation. J Biol Chem 269:7963–7969
Wojcikiewicz RJ, Nakade S, Mikoshiba K, Nahorski SR (1992) Inositol 1,4,5-trisphosphate receptor immunoreactivity in SH-SY5Y human neuroblastoma cells is reduced by chronic muscarinic receptor activation. J Neurochem 59:383–386
Oberdorf J, Webster JM, Zhu CC, Luo SG, Wojcikiewicz RJ (1999) Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway. Biochem J 339:453–461
Lee HS, Lee SA, Hur SK, Seo JW, Kwon J (2014) Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. Nat Commun 5:5128
Zarrizi R, Menard JA, Belting M, Massoumi R (2014) Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells. Cancer Res 74:6499–6508
Yu H, Pak H, Hammond-Martel I, Ghram M, Rodrigue A, Daou S et al (2014) Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci U S A 111:285–290
Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G et al (2010) The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol Cell Biol 30:5071–5085
Baughman JM, Rose CM, Kolumam G, Webster JD, Wilkerson EM, Merrill AE et al (2016) NeuCode proteomics reveals Bap1 regulation of metabolism. Cell Rep 16:583–595
Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S et al (2012) O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metab 16:226–237
Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M et al (2017) BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546:549–553
Bononi A, Yang H, Giorgi C, Patergnani S, Pellegrini L, Su M et al (2017) Germline BAP1 mutations induce a Warburg effect. Cell Death Differ 24:1694–1704
Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A et al (2017) PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth. Nature 546:554–558
Worby CA, Dixon JE (2014) PTEN. Annu Rev Biochem 83:641–669
Carnero A, Paramio JM (2014) The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol 4:252
Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N et al (2015) PTEN: multiple functions in human malignant tumors. Front Oncol 5:24
Bittremieux M, Parys JB, Pinton P, Bultynck G (2016) ER functions of oncogenes and tumor suppressors: modulators of intracellular Ca2+ signaling. Biochim Biophys Acta 1863: 1364–1378
Bononi A, Bonora M, Marchi S, Missiroli S, Poletti F, Giorgi C et al (2013) Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ 20:1631–1643
Furuichi T, Yoshikawa S, Miyawaki A, Wada K, Maeda N, Mikoshiba K (1989) Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342:32–38
Acknowledgements
TV is recipient of a postdoctoral fellowship of the Research Foundation—Flanders (FWO). Work performed in the laboratory of the authors was supported by research grants of the FWO, the Research Council of the KU Leuven and the Interuniversity Attraction Poles Programme (Belgian Science Policy). JBP is member of the Transautophagy COST action CA15138.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Parys, J.B., Vervliet, T. (2020). New Insights in the IP3 Receptor and Its Regulation. In: Islam, M. (eds) Calcium Signaling. Advances in Experimental Medicine and Biology, vol 1131. Springer, Cham. https://doi.org/10.1007/978-3-030-12457-1_10
Download citation
DOI: https://doi.org/10.1007/978-3-030-12457-1_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-12456-4
Online ISBN: 978-3-030-12457-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)