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

Figures & data

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).

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].

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.

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].

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Data availability statement

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