Type 3 IP3 receptor: Its structure, functions, and related disease implications

ABSTRACT

Cell-fate decisions depend on the precise and strict regulation of multiple signaling molecules and transcription factors, especially intracellular Ca²⁺ homeostasis and dynamics. Type 3 inositol 1,4,5-triphosphate receptor (IP3R3) is an a tetrameric channel that can mediate the release of Ca²⁺ from the endoplasmic reticulum (ER) in response to extracellular stimuli. The gating of IP3R3 is regulated not only by ligands but also by other interacting proteins. To date, extensive research conducted on the basic structure of IP3R3, as well as its regulation by ligands and interacting proteins, has provided novel perspectives on its biological functions and pathogenic mechanisms. This review aims to discuss recent advancements in the study of IP3R3 and provides a comprehensive overview of the relevant literature pertaining to its structure, biological functions, and pathogenic mechanisms.

KEYWORDS:

• IP3R3
• IP₃ receptor
• Ca²⁺ signaling
• apoptosis
• cancer

Introduction

Calcium ion (Ca²⁺), one of the second messengers, is responsible for intracellular signal transduction and regulates a number of biological processes, such as cell proliferation [1], differentiation [2], migration [3], and apoptosis [4]. In other words, the role of Ca²⁺ in maintaining the organism’s homeostasis and normal physiological functions is of utmost significance. There are generally two pathways for the generation of cellular Ca²⁺ signals: the influx of Ca²⁺ from the extracellular environment and the release of Ca²⁺ from intracellular storage [5]. Distinct transporters facilitate these processes, which are tightly regulated by numerous proteins [6].

In vivo, inositol 1,4,5-triphosphate (IP₃) is a chemical compound that cells produce in response to external stimuli. By binding to the IP₃ receptor (IP₃R), IP₃ functions as an intracellular chemical signal that induces the release of Ca²⁺ from the endoplasmic reticulum [7]. There are three distinct isoforms of IP₃Rs in mammalian cells, namely IP3R1, IP3R2, and IP3R3, which are respectively encoded by the genes ITPR1, ITPR2, and ITPR3 [8]. Depending on the tissue type, cellular localization, and developmental stage, the three IP₃R isoforms with significant sequence homology display different relative expression levels [9,10,11]. For instance, IP3R1 shows strong expression in neurons [12,13], and IP3R2 exhibits high expression in cardiomyocytes and hepatocytes [14,15], while IP3R3 is highly expressed in rapidly dividing cells [16]. Furthermore, there are differences in the regulation and function of IP₃R isoforms. An evident example is the fact that each of the three isoforms exhibits varying affinity for the ligand IP₃ (IP3R2 > IP3R1 > IP3R3) [9,17,18]. Therefore, disturbances in the regulation or function of different IP₃R isoforms will result in distinct pathophysiological outcomes [16]. Many studies have demonstrated how crucial a role IP3R3 plays in diseases such as tumors [19,20], exocrine dysfunction [21, 22], autoimmune diseases [23,24,25], and infections [26]. This review will offer a comprehensive overview of IP3R3, highlighting its key characteristics, such as its structure, function, and pathogenic mechanism.

Structure of IP3R3

The ITPR3 gene, which is located at 6p21.31, consists of sixty-two exons [27] and has two transcripts. Both transcripts of differing lengths (9,079 and 9,870 bps) can encode IP3R3. The structure of the IP3R3 monomer comprises three distinct functional domains, namely the IP₃ binding region, the coupling region, and the channel domain (Figure 1a) [28]. Apart from the binding core domain, the IP₃ binding domain also contains a suppressor domain [8] that lowers the affinity of the IP3R3 for IP₃ [29] but is essential for the channel to open in response to its ligand [30]. The coupling region contains interaction sites for many intracellular regulators and interacting proteins [31]. The channel domain contains a transmembrane region formed by six helices and a C-terminal tail [8,32,33]. The prevailing belief is that these helices assume the responsibility of anchoring the receptor to the membrane while simultaneously establishing a functional channel [34]. Additionally, there is a strong possibility that the C-terminal cytoplasmic region just following the transmembrane region contributes supportively to the association among the subunits [35,36]. The full-length human type 3 IP₃R is a tetrameric channel composed of 2,671 residues per subunit with a large amino-terminal cytoplasmic domain (CD), a transmembrane domain (TMD), and a C-terminal cytoplasmic domain (CTD) [37,38]. The large CD can be further divided into several structural domains that span from amino-terminus to the carboxyl-terminus. These domains include two β-trefoil domains (β-TF1, β-TF2), an armadillo repeat domain (ARM1), the first segment of the central linker domain (CLD), the second armadillo repeat domain (ARM2), the second segment of the CLD, and the third armadillo repeat domain (ARM3). β-TF1 primarily constitutes the IP₃ binding suppressor domain [29]. Besides, β-TF1 of one subunit interacts with β-TF2 of the neighboring subunit forming a rim around the 4-fold symmetry axis known as the βTF ring [38–40]. The βTF ring contains several residues involved in IP₃ binding, and its conformation undergoes changes in different states, consequently influencing the entire channel [38]. Bulging from the CLD and positioned in parallel with the membrane surface, the ARM2 interacts with ARM1 of the neighboring subunit, jointly forming the outer periphery of the receptor with the CLD [39]. After the large CD, there is a juxtamembrane domain (JD) located on each side of the TMD. At the ARM3-JD interface, there is an activatory Ca²⁺ binding site, which regulates the activation of IP3R3 [40]. The CTD is located at the very end closest to the carboxyl-terminus (Figure 1a) [38,39]. For IP3R1, the CTD was proposed to transmit the conformational changes triggered by IP₃ at the N-terminal domain to the JD [41]. However, a study on IP3R3 indicated that the CTD is not necessary for channel opening [40]. Recent cryo-electron microscopy studies have clarified the 3D structure of IP3R3 in different states, such as ligand-free, IP₃-bound, Ca²⁺-bound, and ATP-bound [38–40]. Here, we present the structure of IP3R3 in the IP3-bound state (Figure 1b).

Figure 1. (A) functional domains and structural domains of IP3R3. (B) Cryo-EM structure of human IP3R3 in an IP₃-bound state (PDB entry ID: 6DRC).

Functions of IP3R3

Benefiting from its intracellular localization and pivotal position within the cellular regulatory network, IP3R3 possesses important functions, including signal transduction, cell-fate regulation, drug resistance, and cytoskeleton remodeling. As illustrated in Figure 2, various receptors located on the cell membrane recognize distinct extracellular signaling molecules, initiating a series of reactions that result in the generation of IP₃. Subsequently, IP₃ binds to IP3R3, which is located in the endoplasmic reticulum, triggering the release of Ca²⁺ and leading to fluctuations in its concentration. These transient fluctuations in the Ca²⁺ concentration are recognized by Ca²⁺ sensors, ultimately driving a variety of biological processes. During the aforementioned process, the channel activity of IP3R3 is rigorously regulated by molecules from diverse origins. We have summarized the relevant functions of IP3R3 in Table 1.

Figure 2. The functional role of IP3R3. IP3R3 binds to IP₃ generated in response to extracellular stimuli, leading to changes in intracellular Ca²⁺ concentration. Ca²⁺ sensors recognize fluctuations in Ca²⁺ concentration and transmit signals to downstream proteins, ultimately regulating a wide range of biological processes.

Table 1. Related function of IP3R3.

Function	Partners	Description
Signal Transduction	-	IP3R3 preferentially transmits apoptotic Ca^2+ signals into mitochondria [42].
	-	The release of neurotransmitters or neuropeptide may be regulated by IP3R3 [43].
	-	ITPR3 contributes significantly to dopaminergic transmission [44].
Cell-Fate Regulation	BAP1	BAP1 binds, deubiquitylates, and stabilizes IP3R3 to promote cell apoptosis [45].
	NF-κB/CD44 pathway	By accelerating cell cycle transformation and inducing EMT, ITPR3 aided bladder cancer proliferation and metastasis [20].
	BBOX1	By suppressing IP3R3-mediated ER calcium release, the depletion of BBOX1 causes apoptosis and impaired cell-cycle progression in TNBC cells [46].
	FBXL2/NS5A	NS5A viral protein forms a trimeric complex with IP3R3 and FBXL2 to inhibit virus-induced apoptosis [47].
	PTEN	PTEN competes with FBXL2 for IP3R3 binding, preventing cell death [19].
	-	Increased ITPR3 expression in CCA promotes cell proliferation and migration [48].
	-	The IP3R3-Ca^2+ pathway is required for NO-induced cardiomyocyte differentiation of ES cells [49].
	BCKa	The link between IP3R3 and BKCa channels is critical for cancer cell proliferation [50].
	-	ITPR3 helps to maintain HCC by promoting resistance to apoptosis [51].
	STAT3	STAT3 modulates ER Ca^2+ release through IP3R3 to prevent apoptosis [52].
	-	Silencing IP3R3 increased apoptosis in colorectal, ovarian, and clear renal cell carcinoma [53].
	NgBR	Dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation [54].
	-	The expression of IP3R3 enhanced human BC cell migration [55].
	-	IP3R3 expression level inversely correlates with apoptosis degree in CACO-2 colon cancer cells [56].
	-	IP3R3 inhibits apoptosis during mouse embryonic stem cell differentiation [57].
	-	Caffeine blocks glioblastoma invasion and extends survival by inhibiting IP3R3 calcium release channel [58].
	Ets-1	IP3R3 is important for CD4 T cell activation and differentiation [59].
	-	IP3R3-mediated intracellular Ca^2+ release promotes the differentiation of GCPs [60].
Drug Resistance	SMARCA4/2	SMARCA4/2 deficiency impairs chemotherapeutic-induced apoptosis by reducing IP3R3 expression and Ca^2+ release [61].
	-	Chemotherapy increases IP3R3 expression in neuroblastoma cells significantly [62].
Cytoskeleton Remodeling	ARHGAP18/RhoA/Mdia1/FAK	IP3R3 can coordinate the remodeling of profilin cytoskeleton organization [63].
	EB3	EB3-mediated IP3Rs-microtubule interaction regulates endothelial permeability [64].

Signal transduction

One of the most important functions of IP3R3 is the transduction of intracellular calcium signals. Recent research has demonstrated that IP3R3 plays a significant role in the transmission of Ca²⁺ signaling during apoptosis, even in cases where it is not the predominant isoform [42]. This preference is attributed to the abundant distribution of IP3R3 at the mitochondria-associated ER membrane (MAM) [42,65,66]. In transducing calcium signaling, IP3R3 is regulated by a wide range of signals, including Ca²⁺ [67,68], phosphorylation [69], ATP [70–72], and various proteins [73–75]. Apart from its role in calcium signaling, IP3R3 has also been linked to the release of neurotransmitters. The research conducted by Sharp et al. indicated that IP3R3 May have a function in regulating the release of neurotransmitters or neuropeptides in terminals within specific basal forebrain and limbic system nuclei [43]. An additional study has demonstrated a significant contribution of IP3R3 to the transmission of dopaminergic synapses [44].

Cell-fate regulation

Cell proliferation

Nogo-B receptor (NgBR) is a subunit of cis-prenyltransferase that is capable of promoting the proliferation of vascular smooth muscle cells (VSMCs) by disrupting MAM and increasing IP3R3 phosphorylation [54]. Moreover, additional evidence supporting the close association between IP3R3 and cell proliferation can be observed in cancer cells. Zhang et al. found that IP3R3 activates the NF-κB/CD44 pathway, leading to the promotion of bladder cancer cell proliferation [20]. Upregulation of IP3R3 in cholangiocarcinoma results in the enhancement of malignant characteristics, including cell migration, cell proliferation, and mitochondrial Ca²⁺ signaling [48]. BKCa is well-known for being a crucial regulator of membrane excitability in a broad range of cells and tissues [76]. The BKCa channel and IP3R3 are functionally and molecularly linked, which can facilitate the proliferation of breast cancer cells [50].

Cell migration

IP3R3 has the ability to regulate the migratory capacity of human breast cancer cells by modifying their calcium signature. Silencing of IP3R3 triggered an oscillating calcium signaling profile, resulting in a significant attenuation of the cellular migratory capacity of MCF-7, MDA-MB-231, and MDA-MB-435S breast cancer cell lines [55]. On top of that, another study found that caffeine can prevent glioblastoma migration and invasion by inhibiting IP3R3 [58].

Cell differentiation

Besides its effects on cell proliferation and migration, IP3R3 has been shown to exert an influence on cell differentiation. In a study by Wei et al., the role of Ca²⁺ signaling in cardiomyocyte (CM) differentiation of mouse embryonic stem (ES) cells induced by nitric oxide (NO) was investigated. Their study demonstrated that the IP3R3-Ca²⁺ pathway is necessary for NO-induced CM differentiation of ES cells [49]. A comparative study revealed that intracellular calcium release via IP3R2 and IP3R3 promotes the differentiation of granule cell precursors within a specific interval of postnatal development in the cerebellum [60]. IP3R3 is also implicated in the differentiation of immune cells, with particular importance demonstrated in the activation and differentiation of CD4 T cells [59].

Cell apoptosis

Last but not least, the most pervasive role of IP3R3 in cell-fate regulation is to influence cell apoptosis. Related studies have established that some proteins serve to govern cell apoptosis by regulating the IP3R3-mediated Ca²⁺ signaling pathway. The potent tumor suppressor gene known as BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes. BAP1 can regulate Ca²⁺ release from the ER to the cytoplasm and mitochondria to promote cell apoptosis by binding, deubiquitylating and stabilizing IP3R3 [45]. The enzyme gamma-butyrobetaine hydroxylase 1 (BBOX1) catalyzes the conversion of gamma-butyrobetaine to L-carnitine. In triple-negative breast cancer cells, its depletion suppresses the release of Ca²⁺ from the ER that is regulated by IP3R3, leading to cell apoptosis and disruption of cell-cycle progression [46]. Furthermore, it has been revealed that the interaction of PTEN and STAT3 with IP3R3 underpins their anti-apoptotic functions [52]. Exogenous proteins can also interact with IP3R3 to control cell apoptosis. An IP₃-independent molecular mechanism is described by the researchers, in which the viral protein NS5A forms a trimeric complex with IP3R3 and FBXL2, promoting the degradation of IP3R3, inhibiting virus-induced apoptosis, and establishing chronic infection [47].

Drug resistance

The development of chemoresistance represents a significant challenge in the effective management of cancer, as it is a primary contributor to disease recurrence and treatment failure. Despite the fact that there are limited studies on the relationship between IP3R3 and chemoresistance, the available evidence suggests that IP3R3 may play a role in chemoresistance. In ovarian and lung cancers, a team of researchers found that the loss of SMARCA4/2 limits IP3R3-mediated Ca²⁺ flux from the ER to mitochondria, which results in resistance to chemotherapy-induced apoptosis [61]. A different study demonstrated that exposure to cisplatin significantly upregulated the expression of IP3R3 in SH-SY5Y cells, confirming the pivotal involvement of IP3R3 in the response of neuroblastoma cells to chemotherapy [62].

Cytoskeleton remodeling

Cellular migration is accompanied by changes in cell morphology, and these changes are intricately tied to the remodeling of the cytoskeleton, which is strongly influenced by the level of intracellular Ca²⁺ [77]. In their previous work, the researchers found that IP3R3 can regulate the availability of intracellular Ca²⁺ and to coordinate the remodeling of the profilin cytoskeleton organization via the ARHGAP18/RhoA/mDia1/FAK pathway [63]. The EB3-mediated interaction between IP₃Rs and microtubules plays a crucial role in assembling IP₃Rs into functional clusters for Ca²⁺ signaling, ultimately regulating endothelial permeability that is dependent on microtubules [64].

IP3R3 and diseases

As a fundamental contributor in Ca²⁺ signal transduction, the stability of expression and function of IP3R3 is intricately intertwined with the health of the organism. Existing research indicates that IP3R3 is linked to a variety of diseases, including but not limited to exocrine dysfunction, autoimmune disease, neurological disease, infection, and cancer (Figure 3). Not only can dysregulation of IP3R3 expression contribute to the initiation and advancement of diseases, but also variants in the IP3R3 gene have emerged as causal factors for distinct pathological states and diverse disease outcomes. An outline of the disease-related human IP3R3 variants is presented in Table 2.

Figure 3. Overview of IP3R3-related diseases. IP3R3 is implicated in the pathogenesis and progression of a variety of diseases, predominantly encompassing neurological disorders, infection, cancer, autoimmune diseases and exocrine dysfunction.

Table 2. IP3R3 variants associated with disease.

rsID	Variant Type	Nucleotide change	AAchange	Disease
-	Missense Variant; Missense Variant	G>T; G>A	Arg149Leu; Arg64His	Head and neck squamous cell carcinoma [78]
rs3748079; rs2229634	Upstream Transcript Variant; Synonymous Variant	3992C>T; 54025C>A/G/T	N/A; Gly756=	Cervical squamous cell carcinoma [79]
rs3748079	Upstream Transcript Variant	3992C>T	N/A	Systemic lupus erythematosus; Rheumatoid arthritis; Graves’ disease [25]
rs2296336	Intron Variant	52505C>A/G/T	N/A	Type 1 diabetes [21]
rs2229634	Synonymous Variant	54025C>A/G/T	Gly756=	Kawasaki disease [80]
-	Missense Variant; Missense Variant	1843 G>A; 7570C>T	Val615Met; Arg2524Cys	Charcot-Marie-Tooth disease [81]
rs116454384	Intron Variant	62220C>G/T	N/A	Non-small cell lung cancer [82]
rs2229642	Missense Variant	75317C>A/G	Leu2436Ile	Breast cancer [83]
-	Missense Variant	4271C>T	Thr1424Met	Inherited peripheral neuropathies [84]
rs9394159; rs4711332	Intron Variant; Intron Variant	34007A>G/T; 11244A>C/G/T	N/A; N/A	Graves’ disease [85]
rs999943	Intron Variant	40578A>G	N/A	Obesity [86]
rs10947428	Intron Variant	62903T>C	N/A	Eczema [87]
rs71565398	Intron Variant	17575C>G/T	N/A	Asthma; Attention deficit hyperactivity disorder [88]
rs10947428	Intron Variant	62903T>C	N/A	Allergic reaction [89]
rs2229637	Synonymous Variant	59403 G>A	Pro1069=	Venous thromboembolism [90]
rs942637	Intron Variant	68956T>A/C/G	N/A	Multiple sclerosis [91]
rs2296328; rs2296340; rs4713653; rs9296097	Intron Variant; Intron Variant; Intron Variant; Intron Variant	67122C>T; 46317 G>A; 63439C>A/G/T; 755988 G>A/T	N/A; N/A; N/A; N/A	Coronary heart disease [92]
rs2296742; rs3818523; rs3818527; rs3818530	Intron Variant; Intron Variant; Intron Variant; Intron Variant	75638 G>A/C; 76216 G>A; 76880 G>A/C; 77067C>G	N/A; N/A; N/A; N/A	Rheumatoid arthritis [93]
rs4711332	Intron Variant;	11244A>C/G/T	N/A	Hepatitis B [94]
rs4713646	Intron Variant	22368C>A/G/T	N/A	Malignant testicular germ cell cancer [95]
rs3818528; rs4713653; rs4713654	Intron Variant; Intron Variant; Intron Variant	76936 G>A/C/T; 63439C>A/G/T; 63496A>G/T	N/A; N/A; N/A	Rheumatoid arthritis [96]
rs3818528; rs4713653; rs4713654; rs6935686	Intron Variant; Intron Variant; Intron Variant; Intron Variant	76936 G>A/C/T; 63439C>A/G/T; 63496A>G/T; 29972C>T	N/A; N/A; N/A; N/A	Rheumatoid arthritis [97]
rs2077163	Missense Variant	52752C>G/T	His721Gln	Type 1 diabetes [98]
-	Missense Variant; Missense Variant; Missense Variant	7570C>T; 5549 G>A; 4882T>C	Arg2524Cys; Arg1850Gln; Phe1628Leu	Immune deficiency Disease [99]
-	Deletion Variant	GTGCTGAGCGTT>-	-	Multiple sclerosis [100]
rs499384	-	G>A	-	Irritant contact dermatitis [101]

-: not specific, N/A: The protein sequence is not affected.

Exocrine dysfunction

The primary function of exocrine glands is the synthesis and release of secretions that aid in food digestion, mucosal defense, thermoregulation, lubrication, and nutrition [102]. The cardinal functions of exocrine cells, such as regulated exocytosis and secretion of fluids and electrolytes, are accomplished through the synergistic interplay of calcium signaling and other signaling pathways, with a particular emphasis on the cyclic AMP (cAMP) pathway [103]. Mice lacking IP₃R types 2 and 3 (itpr2-/- & itpr3-/- double-knockout mice) have no tear production in either the parasympathetic or sympathetic pathways [104]. Similarly, the impact of IP3R3 on exocrine has been observed in humans. As found by Teos et al., the inability of Sjögren’s syndrome patients to secrete saliva can be attributed to deficiencies in IP3R2 and IP3R3 [105]. In addition to affecting the secretion of tears and saliva, IP3R2 and IP3R3 also impact the secretion of olfactory mucus. Observations of IP3R2-R3 double-knockout mice showed decreased olfactory mucus secretion and nasal abnormalities [106].

IP3R3 has also been implicated in digestion-related exocrine diseases. Approximately 80% of the IP₃Rs in cholangiocytes are IP3R3, which is the only isoform present in the apical area where secretion takes place and is the predominant intracellular calcium-release channel in these cells [107]. The absence of IP3R3 in cholangiocytes has been observed in patients with primary biliary cirrhosis, sclerosing cholangitis, biliary atresia, and biliary obstruction, as well as in different animal models of ductular cholestasis [108]. The further study revealed the regulatory mechanism of IP3R3 expression in cholangiocytes. The binding of the transcription factor NRF2 to the promoter of ITPR3 has been shown to inhibit the expression of IP3R3, resulting in decreased calcium signaling and bile duct secretion [109].

Autoimmune disease

Autoimmune disease refers to the disease caused by the body’s immune response to autoantibodies, resulting in damage to its own tissues. Nearly a hundred distinct autoimmune disease have been identified, including but not limited to rheumatoid arthritis (RA), type I diabetes (T1D), multiple sclerosis (MS), and systemic lupus erythematosus (SLE), which are among the most common ones [110]. In a Japanese population, systemic lupus erythematosus, rheumatoid arthritis and Graves’ disease are all related to the rs3748079 SNP, which is located in the promoter region of ITPR3 [25]. Another study conducted on a Swedish population suggested that the variation at rs2296336 within introns of ITPR3 may have an impact on risk for type I diabetes through an effect on alternative splicing [21].

Neurological disorders

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease whose pathological hallmarks include cell loss in the substantia nigra and other brain areas, as well as neural inclusion in the form of Lewy bodies and Lewy neurites [111]. The multifunctional protein DJ-1 is localized in the mitochondria and is involved in a variety of cellular processes [112]. A recent study revealed that the IP3R3-Grp75-VDAC1 complexes at MAM, which are associated with the pathogenesis of PD, physically interact with and depend on DJ-1 as one of their components [113].

Charcot-Marie-Tooth disease (CMT), another neurological disorder in which IP3R3 has been implicated, is characterized by progressive distal sensory and motor dysfunction [114]. A study based on whole-exome sequencing confirmed that ITPR3 is a gene that causes CMT and changes the balance of Ca²⁺ in the development of the disease [81].

Major depressive disorder (MDD) is a clinically diagnosed disorder that is usually accompanied by prolonged periods of depressed mood or anhedonia, along with physical and cognitive symptoms [115]. A meta-analysis prioritized the 269 GWAS depression risk genes and highlighted 12 genes, including ITPR3, that were consistently differentially expressed across three transcriptomic studies of MDD [116].

Furthermore, IP3R3 appears to exhibit an association with the impairments of taste and hearing. It has been reported that Gbc subunits have the ability to activate PLCb2, leading to the production of IP₃, which in turn triggers the release of Ca²⁺ via IP3R3 located on the ER membrane. Mice lacking PLCb2 or IP3R3 exhibit a significant deficiency in their capacity to detect sweet, bitter, and umami tastes, highlighting the crucial role of the IP₃-mediated calcium signal cascade in taste signal transduction [117–119]. Despite the lack of direct evidence linking IP3R3 to dysaudia, researchers have found that alterations in, as well as the maintenance of, all three IP3R isoforms’ expression during post-natal development of the rat cochlea, suggest that IP3R-mediated calcium signaling may be involved in cochlear development [120].

Infection

Chlamydia trachomatis is an obligate intracellular bacterium that can be released either by lysis of the host cell or extrusion of the intact inclusion at the end of its intracellular developmental cycle. When the expression of host ITPR3 was silenced using siRNA, there was a noticeable reduction in the extrusion of Chlamydia trachomatis [26]. Salmonella exploits macrophages as a vehicle for hematogenous and lymphatic dissemination, resulting in localized infections as well as systemic ones. ITPR3 has been identified as a host candidate factor in macrophages that imparts resistance against Salmonella infections, and it is a promising therapeutic target for such infections [22]. Astroviruses, which cause acute gastroenteritis in children and individuals with immunocompromised state, are tiny, nonenveloped viruses with a single-stranded positive-sense RNA genome. In a study using RNA interference technology, the possible role of a few of the identified proteins, including IP3R3, in the replication cycle of astroviruses was investigated. The findings indicated that silencing of ITPR3 expression significantly decreased the levels of genomic and antigenomic RNA for Yuc8, the synthesis of the structural protein VP90, and virus yield [121].

Cancer

Given the known link between IP3R3 and cell apoptosis, it is not surprising to suppose that changes in its expression or function may play a role in tumor development. So far, researchers have investigated the involvement of IP3R3 in certain types of cancer. The upregulation of ITPR3 expression in cholangiocytes has been observed in cholangiocarcinoma, and this alteration contributes to malignant features, including cell proliferation and migration, as well as enhanced mitochondrial Ca²⁺ signaling [48]. Moreover, the expression of ITPR3 in hepatocellular carcinoma (HCC) has been found to be inversely correlated with the mitotic and apoptotic indices, indicating that ITPR3 could be involved in the maintenance of HCC by enhancing apoptosis resistance [51].

IP3R3 has also shown potential as a biomarker for cancer. Wu et al. found that ITPR3 rs116451384 appears to impact the progression of non-small cell lung cancer (NSCLC) by regulating gene expression, and may be a predictor for NSCLC survival [82]. In another study on cervical squamous cell carcinoma (CSCC), the haplotype in the ITPR3 gene was identified as a potential marker for genetic susceptibility to CSCC [79]. Apart from the aforementioned cancers, ITPR3 has been proposed as a potential marker in pancreatic cancer [122], breast cancer [83,123], and head and neck squamous cell carcinoma [124]. To gain a deeper understanding of the association between IP3R3 and cancer, we provide a comprehensive summary of the relevant studies investigating the role of IP3R3 in various types of cancers (Table 3).

Table 3. IP3R3 in cancer.

Cancer types	Expression	Description
Glioblastoma	↑	IP3R3 expression is increased in U87MG, U178MG, U373MG, T98G, M059K cell lines, and primary tissues [58].
Head and neck squamous cell carcinoma	↑	Shorter latency to second primary malignancy formation was observed to be substantially associated with high ITPR3 expression levels 124
Bladder carcinoma	↑	Bladder cancer tissue and cells exhibit higher ITPR3 expression [20].
Cholangiocarcinoma	↑	Upregulation of IP3R3 enhances malignant features in cholangiocarcinoma [48].
Cholangiocarcinoma	↑	ITPR3 overexpression may drive CCA progression [125].
Gastric cancer	↑	IP3R3 may act in the peritoneal dissemination of gastric cancers [126].
Hepatocellular carcinoma	↑	The maintenance and the resistance to apoptosis of HCC are both impacted by IP3R3 [51].
Breast cancer	↑	IP3R3 expression is linked to breast cancer prognosis [123].
Breast cancer	↑	Downregulation of IP3R3 reduces breast cancer cell migration [55].
Colorectal cancer	↑	IP3R3 is linked to the aggressiveness of colorectal carcinoma [56].
Colorectal cancer	-	The ITPR3/calcium/RELB axis plays a role in CRC metastatic colony formation [127].
Breast cancer	-	BKCa-IP3R3 coupling is essential for tumor cell proliferation [50].
Breast cancer	-	IP3R3-induced Ca2+ signaling participates in estradiol-induced growth of breast cancer epithelial cells [128].
Breast cancer	-	ITPR3 may predict breast cancer risk in the Chinese population [83].
Non-small cell lung cancer	-	Functional variants of ITPR3 may predict survival in NSCLC patients [82].
Cervical squamous cell carcinoma	-	ITPR3 may be a marker for CSCC genetic susceptibility 79.
Pancreatic cancer	-	ITPR3 may serve as a therapeutic target and biomarker for human pancreatic cancer [122].
Head and neck squamous cell carcinoma	-	ITPR3 was mutated in recurrent/metastatic HNSCC [78].
Testicular germ cell tumor	-	The association ITPR3 rs4713646 with TGCT was evident in the GWAS analysis [95].

Other diseases

Thanks to the establishment of large-scale population cohort resources and the rapid advancement of high-throughput sequencing techniques, beyond the mentioned major disease categories, the association between IP3R3 and other diseases has been gradually unveiled. For example, a study involving 93 Kawasaki disease (KD) patients and 680 healthy controls demonstrated an association between the single nucleotide polymorphism of ITPR3 (rs2229634) and an increased risk of coronary artery aneurysm development in children with KD [80]. In addition, a substantial number of other studies have reported potential links between distinct ITPR3 variants and chronic diseases such as obesity [86], eczema [87], asthma [88], and coronary heart disease [92]. However, this merely hints at the potential role of IP3R3 in these complex diseases; the specific functions and molecular mechanisms still demand further exploration.

Conclusion and outlook

As an intersection and central hub for numerous signaling pathways and biological processes, IP3R3 is subject to regulation by a multitude of molecules and mechanisms, influencing its activity and stability. Recent advances in the study of the IP3R3 structure have unveiled a plethora of insights into its gating behavior and regulatory mechanisms, thereby providing valuable elucidation for our comprehension of the interrelationship between its channel architecture and diverse functional characteristics. Nonetheless, the specific mode by which a multitude of regulatory proteins and molecules interact with IP3R3, along with the underlying structural basis that supports their impact on the function of IP3R3, remains inadequately clarified. Additionally, serving as a crucial participant in intracellular Ca²⁺ signaling, IP3R3 assumes a vital role in various cellular functions. The aberrant release of Ca²⁺ resulting from both its expression dysregulation and genetic variants is associated with a diversity of pathological conditions. Abundant evidence points to the anomalous expression or genetic variants of IP3R3 across a range of cancers, suggesting it may function as a critical Ca²⁺ channel for cancer cell survival. Nevertheless, differences may exist in the molecular mechanisms through which IP3R3 impacts malignant characteristics in distinct cancer types, and the complete regulatory network is still not fully understood. It is intriguing that the unique expression and co-expression of the three IP3R subtypes in different cell types might result in discrepancies in intracellular Ca²⁺ homeostasis regulation. In light of this, while delving into the investigation of IP3R3, it might be judicious to also focus on alternative IP3R subtypes. An enhanced understanding of the action mechanisms of homomeric or heteromeric tetramers formed by IP3R3 in diverse diseases will aid in the development of novel therapeutic targets and biomarkers.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

This work was supported by grants from the Natural Science Foundation of Hainan Province of China (822MS179), the Natural Science Foundation of Fujian Province of China (2021J011266), and the National Natural Science Foundation of China (82260161).