Affinage

ITPR1

Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 · UniProt Q14643

Length
2758 aa
Mass
313.9 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITPR1 encodes the IP3-gated Ca2+ release channel that assembles as a homotetramer on the ER membrane and serves as the principal route for IP3-triggered Ca2+ mobilization, most prominently in cerebellar Purkinje cells where its transcript is most abundant and is transported to distal dendrites (PMID:8081710, PMID:25821909). Channel output is set by ligand affinity and by a network of regulators acting on its suppressor and C-terminal domains: carbonic anhydrase-8 allosterically inhibits the channel and limits its phosphorylation and cytosolic Ca2+ release (PMID:25734498), ERp44 binds the L3V domain to suppress Ca2+ release (PMID:22183808), whereas NCS1 binding to the suppressor domain and ORP4L binding to the carboxyl terminus potentiate IP3-driven gating (PMID:31659121, PMID:31648575). Post-translational control includes MAPK/ERK2 phosphorylation during M-phase that is required for normal egg Ca2+ oscillations (PMID:17038520), Src phosphorylation at Tyr353 that stabilizes the protein in lipid-stressed hepatocytes (PMID:33358861), calpain cleavage that produces a C-terminal pore fragment with IP3-independent gating in injured Purkinje neurons (PMID:21859719), and ubiquitin-dependent proteasomal degradation via epsin adaptors in atherogenic endothelium (PMID:32770009). Physiologically, ITPR1-mediated ER Ca2+ release drives Purkinje-cell firing and olivo-cerebellar motor coordination (PMID:24109434), endothelial calcineurin/NFAT/eNOS signaling and blood pressure control (PMID:27402766), glucagon-stimulated intrahepatic lipolysis and gluconeogenesis (PMID:32132708), lymphatic muscle pacemaking via ANO1 (PMID:37851027), GI tract contractility (PMID:30382364), and ER-to-mitochondria Ca2+ transfer through an IP3R1-GRP75-VDAC1 complex (PMID:35344886). Genetically, ITPR1 haploinsufficiency causes spinocerebellar ataxia type 15, while missense changes act through loss of channel function with dominant-negative effects or through gain-of-function increases in IP3-binding affinity that underlie SCA29 (PMID:17590087, PMID:27108797, PMID:28620721).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1993 Medium

    Established the cellular and assembly context of the receptor by showing InsP3R1 is the predominant tetrameric IP3/Ca2+ channel in neurons, enriched in Purkinje cell dendrites.

    Evidence In situ hybridization for mRNA localization with tetrameric assembly cited from prior biochemistry

    PMID:8081710

    Open questions at the time
    • Tetrameric stoichiometry cited rather than directly resolved in this study
    • No functional channel readout in the dendritic compartment
  2. 1994 Medium

    Defined the human gene product and its chromosomal locus, providing the molecular foundation for subsequent disease and biochemical work.

    Evidence cDNA cloning, Northern/Western blots, IHC, and chromosomal mapping to 3p25-26

    PMID:7945203

    Open questions at the time
    • No channel function assayed
    • Tissue survey limited to a few cell types
  3. 2006 High

    Showed that cell-cycle kinase signaling directly modifies the channel, linking MAPK/ERK2 phosphorylation to competent Ca2+ oscillations in eggs.

    Evidence In vitro kinase assay with ERK2, phosphosite mutagenesis, and MPM2 reactivity with Ca2+ readouts in mouse and Xenopus eggs

    PMID:17038520

    Open questions at the time
    • Phosphosite identity at residue level not fully mapped here
    • Relevance to somatic cell types untested
  4. 2007 High

    Established ITPR1 dosage as causative for cerebellar ataxia by linking 5' deletions to SCA15 and recapitulating ataxia with reduced Purkinje expression in mice.

    Evidence Linkage, sequence and gene-dosage analysis across human pedigrees and mouse, with Purkinje cell IHC

    PMID:17590087

    Open questions at the time
    • Mechanism by which reduced channel output disrupts Purkinje physiology not resolved here
  5. 2008 High

    Demonstrated that a SCA15 missense mutation alters channel biophysics, showing increased IP3-binding affinity and reduced cooperativity rather than simple loss of function.

    Evidence Reconstitution of P1059L mutant in IP3R-deficient B lymphocytes with IP3-binding and Ca2+ release assays

    PMID:18579805 PMID:21689634

    Open questions at the time
    • Single cell-line context
    • How altered affinity translates to Purkinje pathology unaddressed
  6. 2011 High

    Identified proteolytic remodeling of the channel, showing calpain generates an IP3-independent constitutively active pore fragment relevant to neuronal injury.

    Evidence Single-channel electrophysiology of truncated InsP3R1, ER Ca2+ store measures, and cleavage-specific antibody after cardiac arrest in vivo

    PMID:21859719

    Open questions at the time
    • Contribution of the fragment to in vivo cell death quantitatively unresolved
  7. 2011 High

    Linked IP3R1 Ca2+ release to neuromuscular synapse development and to excitotoxic calpain/caspase activation in cholinergic overactivity.

    Evidence siRNA knockdown in C2C12 and in vivo myasthenic/anti-cholinesterase models with force and gene-expression readouts

    PMID:22031873

    Open questions at the time
    • Upstream IP3-generating receptors at the NMJ not defined
  8. 2011 Medium

    Provided early identification of ERp44 as a direct ER-luminal inhibitor binding the L3V domain, dissociating binding affinity from functional inhibition.

    Evidence Pull-down with the L3V domain, ERp44 cysteine mutagenesis, and Ca2+ imaging in overexpressing HeLa cells

    PMID:22183808

    Open questions at the time
    • Single-lab pull-down
    • Physiological redox context of inhibition not established
  9. 2011 Low

    Tentatively linked IP3R1 Ca2+ release activity to mutant huntingtin aggregation.

    Evidence shRNA knockdown with polyQ aggregation assay and 2-APB analog comparisons

    PMID:22056561

    Open questions at the time
    • Correlation between IICR inhibition and aggregation is weak
    • No reciprocal validation or direct interaction shown
  10. 2013 High

    Resolved how loss of the channel perturbs motor circuits, placing IP3R1 within an olivo-cerebellar pathway whose Purkinje firing patterns drive dystonia.

    Evidence Cerebellum/brainstem-specific conditional KO with in vivo Purkinje firing recordings and circuit inactivation rescue

    PMID:24109434

    Open questions at the time
    • Molecular coupling between Ca2+ loss and altered firing not detailed
  11. 2013 Medium

    Revealed post-transcriptional control of IP3R1 isoforms by the CHERP/ALG-2 splicing machinery.

    Evidence Co-IP, RNA-IP showing direct CHERP-IP3R1 RNA binding, and siRNA-induced exon 41/42 inclusion

    PMID:24078636

    Open questions at the time
    • Functional consequence of the alternative isoforms on channel behavior unresolved
    • Single lab
  12. 2014 High

    Identified ITPR1 as a HIF2alpha transcriptional target driving cytoprotective autophagy and NK resistance in renal carcinoma, extending its role beyond Ca2+ flux per se.

    Evidence Expression profiling, ChIP at the ITPR1 promoter, siRNA dissection with Beclin-1, NK cytotoxicity and in vivo tumor models

    PMID:25297632

    Open questions at the time
    • How ITPR1 Ca2+ signaling mechanistically engages the autophagy machinery not fully defined
  13. 2015 High

    Established mRNA-trafficking control of IP3R1, showing DISC1/HZF transport Itpr1 mRNA to dendrites to support synaptic plasticity.

    Evidence Proteomic interactor screen, RNA-IP for DISC1-ITPR1 mRNA, dendritic co-localization, and Disc1 KO plasticity assays

    PMID:25821909

    Open questions at the time
    • Local translation of Itpr1 in dendrites not directly measured
  14. 2015 High

    Defined carbonic anhydrase-8 as an allosteric channel inhibitor controlling nociceptive Ca2+ signaling.

    Evidence Car8 null and AAV overexpression with pITPR1 immunoblotting, Ca2+ imaging, and pain behavior assays

    PMID:25734498

    Open questions at the time
    • Structural basis of CAR8-suppressor domain inhibition not resolved here
  15. 2016 High

    Placed endothelial IP3R1 upstream of the calcineurin/NFAT/eNOS axis governing vasodilation and blood pressure.

    Evidence EC-specific KO with blood pressure telemetry, vasodilation assays, eNOS and pathway analysis plus human EC knockdown

    PMID:27402766

    Open questions at the time
    • IP3-generating receptors initiating endothelial Ca2+ release not specified
  16. 2017 High

    Demonstrated a distinct gain-of-function disease mechanism in which a suppressor-domain mutation enhances IP3-binding affinity and reshapes Ca2+ signals in SCA29.

    Evidence Exome sequencing plus IP3-binding and Ca2+ imaging of R36C mutant versus WT

    PMID:28620721

    Open questions at the time
    • How enhanced Ca2+ release damages Purkinje cells in vivo not established
  17. 2019 Medium

    Identified positive C-terminal and suppressor-domain regulators (ORP4L, NCS1) that license or potentiate IP3-driven channel activity and downstream mitochondrial Ca2+ signaling.

    Evidence Co-IP, truncation/mutagenesis, blocking peptides, and Ca2+/mitochondrial imaging in Jurkat and MDA-MB231 cells

    PMID:31648575 PMID:31659121

    Open questions at the time
    • Single-lab interaction data for each partner
    • Stoichiometry of regulatory complexes unknown
  18. 2019 High

    Embedded IP3R1 in a GPR40-driven IP3R1/STIM1/Orai1 store-operated pathway that potentiates glucose-stimulated insulin secretion.

    Evidence siRNA of pathway components in MIN6 with SOCE and insulin readouts plus beta-cell STIM1 KO mice

    PMID:31664108

    Open questions at the time
    • Direct physical coupling of IP3R1 to STIM1/Orai1 not demonstrated
  19. 2020 High

    Established a hepatic metabolic role, showing INSP3R1 is required for glucagon-stimulated intrahepatic lipolysis and gluconeogenesis.

    Evidence Liver-specific KO with isotope tracing of pyruvate carboxylase flux and mitochondrial oxidation in rats and mice

    PMID:32132708

    Open questions at the time
    • Link between hepatocyte Ca2+ release and ATGL activation not mechanistically detailed
  20. 2020 High

    Revealed degradative regulation of IP3R1 by epsin adaptors in atherogenic endothelium, with channel loss accelerating atherosclerosis.

    Evidence Co-IP of epsin with ubiquitinated IP3R1, endothelial epsin and IP3R1 KO atherosclerosis models, and double-KO rescue

    PMID:32770009

    Open questions at the time
    • E3 ligase ubiquitinating IP3R1 not identified
  21. 2021 Medium

    Defined Src-mediated Tyr353 phosphorylation as a stability switch for IP3R1 in lipid-stressed hepatocytes affecting mitochondrial health.

    Evidence Site-specific phospho-detection, SU6656 inhibition, siRNA, protein-stability and mitochondrial/apoptosis assays

    PMID:33358861

    Open questions at the time
    • Single-lab pharmacology
    • Mechanism linking phosphorylation to stability not resolved
  22. 2021 Medium

    Connected IP3R1 Ca2+ overload to cardiomyocyte pyroptosis via NLRP3/Caspase-1, modulated by ERp44 binding, in ischemia/reperfusion.

    Evidence IP3R1 siRNA and ERp44 overexpression in MI/R rat and H/R cardiomyocytes with NLRP3 activation epistasis

    PMID:33568649

    Open questions at the time
    • Single-lab study
    • Direct ERp44-IP3R1 binding not re-validated in cardiac context
  23. 2022 High

    Defined the IP3R1-GRP75-VDAC1 ternary complex as the conduit for ER-to-mitochondria Ca2+ transfer driving pathological remodeling in diabetic atria.

    Evidence Proximity ligation assay and mass spectrometry defining the complex, plus GRP75 siRNA and cardiomyocyte-specific KO with Ca2+ imaging

    PMID:35344886

    Open questions at the time
    • Direct biochemical reconstitution of the ternary complex not shown
  24. 2023 High

    Showed IP3R1 generates diastolic Ca2+ transients that activate ANO1 to drive lymphatic muscle pacemaking and pressure-dependent chronotropy.

    Evidence Smooth muscle-specific conditional KO with pressure myography, GCaMP6f imaging, and membrane potential recordings

    PMID:37851027

    Open questions at the time
    • Mechanism setting diastolic IP3 production in lymphatic muscle not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse regulatory inputs (allosteric inhibitors, phosphorylation, proteolysis, degradation, and accessory binders) are integrated to tune channel output across tissues, and how specific missense mutations map onto gain- versus loss-of-function disease outcomes, remains unresolved.
  • No unified structural model linking regulator binding to gating across the suppressor and C-terminal domains
  • Tissue-specific quantitative contribution of each regulatory mode unmeasured
  • Genotype-phenotype rules for SCA15/SCA29/Gillespie not fully defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CAR8CHERPDISC1ERP44GRP75NCS1ORP4LVDAC1
Complex memberships
IP3R1-GRP75-VDAC1 ER-mitochondria Ca2+ transfer complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 InsP3R1 (ITPR1) protein is known to form a tetrameric receptor-channel complex; the homotetramer of InsP3R1 subtype is the predominant form mediating IP3/Ca2+ signaling in neurons, particularly in cerebellar Purkinje cells where InsP3R1 mRNA is most abundantly expressed and translocated to distal dendrites. In situ hybridization for mRNA localization; biochemical knowledge of tetrameric assembly cited from prior work Receptors & channels Medium 8081710
1994 Human InsP3R1 is a ~220 kDa protein (2695 amino acids) expressed in uteri, oviducts, and HL-60 cells, and the ITPR1 gene is localized to chromosomal region 3p25-26. Expression increases during HL-60 differentiation along the neutrophilic lineage. cDNA cloning, Northern blot, Western blot, immunohistochemistry, chromosomal localization by in situ hybridization The Biochemical journal Medium 7945203
2006 IP3R1 is phosphorylated during oocyte maturation and the first cell cycle at an MPM2-detectable epitope by MAPK/ERK2; mutation of the phosphorylation site abrogates this modification. MAPK/ERK pathway activation is required for IP3R1 MPM2 reactivity, and eggs deprived of MAPK/ERK signaling during maturation fail to mount normal Ca2+ oscillations and show compromised IP3R1 function. In vitro phosphorylation assay with MAPK/ERK2, site-directed mutagenesis of phosphorylation site, MPM2 immunoreactivity in mouse and Xenopus eggs, pharmacological inhibition of MAPK/ERK pathway Development (Cambridge, England) High 17038520
2007 Homozygous in-frame deletion within Itpr1 leads to decreased Itpr1 expression in cerebellar Purkinje cells and causes severe autosomal recessive movement disorder (ataxia) in mice; heterozygous deletion of the 5′ part of ITPR1 (exons 1-10, 1-40, or 1-44) causes spinocerebellar ataxia type 15 (SCA15) in humans, establishing ITPR1 haploinsufficiency as the cause. Linkage analysis, sequence analysis, gene dosage analysis in mouse and human pedigrees, immunohistochemistry in Purkinje cells PLoS genetics High 17590087
2008 An ITPR1 missense mutation (P1059L, proline to leucine) in a Japanese SCA15 family results in a functional Ca2+ release channel with approximately twofold higher IP3-binding affinity compared to wild-type IP3R1, with reduced cooperative dependence on IP3 concentration, yet similar B cell receptor-induced Ca2+ signals. Expression of mutant IP3R1 in IP3R-deficient B lymphocyte cell line, IP3 binding affinity assay, Ca2+ release activity measurement Neurology / Biochemical and biophysical research communications High 18579805 21689634
2011 Calpain cleaves InsP3R1 at a unique site to generate a 95-kDa C-terminal fragment (capn-InsP3R1) containing the transmembrane/pore domain; this fragment displays IP3-independent gating and high open probability under optimal cytoplasmic Ca2+ conditions, reduces ER Ca2+ store content, and is generated in cerebellar Purkinje neurons after cardiac arrest in vivo. Single-channel electrophysiology of recombinant truncated InsP3R1, Ca2+ store measurements in N2a cells, cleavage-specific antibody in vivo The Journal of biological chemistry High 21859719
2011 IP3R1-mediated Ca2+ release in skeletal muscle plays a key role in early NMJ development, homeostatic regulation of neuromuscular transmission, and synaptic gene expression; IP3R1 knockdown or blockade increases synaptic strength and AChR subunit expression. In cholinergic overactivity models, IP3R1 mediates NMJ Ca2+ overload and pathological calpain/caspase activation, and its knockdown eliminates this excitotoxicity. siRNA knockdown in C2C12 cells and in vivo mouse models (anti-cholinesterase toxicity and slow-channel myasthenic syndrome); IP3R blockers; isometric force measurements; gene expression analysis The Journal of neuroscience High 22031873
2012 Truncating ITPR1 mutations that encompass the IP3-binding domain do not form functional channels when expressed in a heterologous cell system. The Lys2563del mutant does not form IP3-induced Ca2+ channels but exerts a dominant-negative effect when co-expressed with wild-type ITPR1. Heterologous expression of mutant ITPR1 in cell system, Ca2+ channel activity assay, co-expression dominant-negative experiment American journal of human genetics High 27108797
2013 IP3R1 deficiency specifically in the cerebellum and brainstem (conditional KO) causes dystonia independent of the basal ganglia; cerebellar Purkinje cell (PC) firing patterns (tonic high-frequency complex spikes) are coupled to specific dystonic movements. Dystonia was rescued by inactivation of the cerebellum, inferior olive, or absence of PCs, placing IP3R1 in an olivo-cerebellar motor coordination pathway. Conditional knockout (cerebellum/brainstem-specific Itpr1 KO), electrophysiology in freely behaving mice (PC firing recordings), cerebellar inactivation rescue experiments Frontiers in neural circuits High 24109434
2013 ALG-2 interacts in a Ca2+-dependent manner with CHERP in the nucleus; CHERP knockdown or ALG-2 knockdown alters alternative splicing of IP3R1 pre-mRNA, producing isoforms that include exons 41 and 42. CHERP binds IP3R1 RNA directly (detected by RNA immunoprecipitation), indicating CHERP/ALG-2 regulate IP3R1 isoform production. Co-immunoprecipitation, RNA immunoprecipitation, siRNA knockdown, immunofluorescence, live cell imaging of Ca2+ mobilization The Journal of biological chemistry Medium 24078636
2014 ITPR1 is a direct transcriptional target of HIF2α in clear cell renal carcinoma; HIF2α-driven ITPR1 overexpression activates autophagy in tumor cells in response to NK cell-derived signals, conferring resistance to NK-mediated lysis. Both ITPR1 and Beclin-1 silencing inhibited NK-induced autophagy and increased granzyme B activity. Global gene expression profiling, chromatin immunoprecipitation (ChIP) for HIF2α at ITPR1 promoter, siRNA silencing of ITPR1/Beclin-1, NK cytotoxicity assay, in vivo tumor regression model Cancer research High 25297632
2015 DISC1 directly binds ITPR1 mRNA and, in a complex with the RNA-binding protein HZF, regulates dendritic transport of Itpr1 mRNA in hippocampal neurons. Loss of DISC1 in knockout mice reduces dendritic levels of Itpr1 mRNA, impairing synaptic plasticity. Proteomic screen for DISC1 interactors, RNA immunoprecipitation showing DISC1-ITPR1 mRNA association, co-localization in dendrites, Disc1 knockout mouse analysis, synaptic plasticity measurements Nature neuroscience High 25821909
2015 Carbonic anhydrase-8 (Car8) acts as an allosteric inhibitor of ITPR1 and regulates the ITPR1-cytosolic free calcium pathway. Car8 null mice show increased steady-state ITPR1 phosphorylation (pITPR1) and increased cytoplasmic Ca2+ release, mechanical allodynia, and thermal hyperalgesia. Overexpression of Car8 in nociceptors down-regulates pITPR1 and abolishes pain hypersensitivity. Car8 null mouse characterization, pITPR1 immunoblotting, cytoplasmic Ca2+ imaging, AAV-mediated Car8 overexpression in nociceptors, behavioral pain assays PloS one High 25734498
2016 EC-specific IP3R1 knockout mice are hypertensive and display blunted vasodilation in response to acetylcholine. IP3R1 is upstream of calcineurin; the calcineurin/NFAT pathway is less active and eNOS levels are decreased in IP3R1-deficient endothelial cells, demonstrating that IP3R1-mediated Ca2+ release from the ER is required for Ca2+-dependent eNOS activation and maintenance of normal blood pressure. Endothelial cell-specific IP3R1 knockout mouse, blood pressure telemetry, vasodilation assays, eNOS activity measurement, calcineurin/NFAT pathway analysis in isolated ECs and human EC knockdown Proceedings of the National Academy of Sciences of the United States of America High 27402766
2017 A missense variant (p.Arg36Cys) in the suppressor domain of ITPR1 causes a gain-of-function: the mutant shows significantly higher IP3-binding affinity than wild-type and changes the intracellular Ca2+ signal pattern from a transient to a sigmoidal shape, indicating enhanced Ca2+ release as a novel pathomechanism for SCA29. Whole exome sequencing for variant identification, IP3 binding affinity assay, intracellular Ca2+ signal recording in cells expressing mutant vs. WT ITPR1 Journal of neurology High 28620721
2019 ORP4L interacts with the carboxyl terminus of ITPR1 in Jurkat T cells. ORP4L enables IP3 binding to ITPR1; a truncated ORP4L construct lacking the ITPR1-binding region retains IP3 production capacity but fails to mediate IP3-ITPR1 binding, thereby failing to enhance ER Ca2+ release and mitochondrial Ca2+ oscillations. Co-immunoprecipitation (ORP4L-ITPR1), truncation mutant analysis, Ca2+ imaging, mitochondrial energetics measurements FASEB journal Medium 31648575
2019 Neuronal calcium sensor 1 (NCS1) binds to residues 66–110 on the suppressor domain of InsP3R1; Leu-89 in the hydrophobic pocket of NCS1 is critical for this interaction. NCS1 overexpression increases Ca2+ signaling via InsP3R1, and blocking the NCS1-InsP3R1 interaction reduces Ca2+ signaling. Protein docking, co-immunoprecipitation, blocking peptides, NCS1 Leu-89 mutagenesis, Ca2+ imaging in MDA-MB231 cells The Journal of biological chemistry Medium 31659121
2019 GPR40 activation in pancreatic β-cells mediates potentiation of glucose-induced insulin secretion through an IP3R1/STIM1/Orai1 pathway: knockdown of IP3R1, STIM1, or Orai1 abolishes GPR40-mediated store-operated Ca2+ entry (SOCE) and insulin secretion potentiation. β-cell-specific STIM1 KO mice confirm this pathway in vivo. siRNA knockdown of IP3R1/STIM1/Orai1 in MIN6 cells, SOCE measurement, insulin secretion assay, β-cell-specific STIM1 knockout mouse Scientific reports High 31664108
2020 Glucagon stimulates hepatic gluconeogenesis via INSP3R1-mediated intrahepatic lipolysis: glucagon increases hepatic adipose triglyceride lipase activity, intrahepatic lipolysis, hepatic acetyl-CoA content, pyruvate carboxylase flux, and mitochondrial fat oxidation, all dependent on INSP3R1. Insp3r1-knockout mice fail to show glucagon-mediated reversal of hepatic steatosis and glucose intolerance. Liver-specific Insp3r1 knockout mice, isotope tracing for metabolic fluxes (pyruvate carboxylase flux, mitochondrial oxidation), in vivo metabolic measurements in rats and mice Nature High 32132708
2020 Epsin endocytic adapter proteins interact with ubiquitinated IP3R1 in atherogenic cholesterol-treated endothelial cells and promote its proteasomal degradation. Deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation; genetic reduction of endothelial IP3R1 accelerates atherosclerosis; epsin deletion in IP3R1-reduced mice restores atherosclerotic progression. Co-immunoprecipitation (epsin-ubiquitinated IP3R1), endothelial epsin KO and IP3R1 KO mouse models of atherosclerosis, cell culture ubiquitination/degradation assays Nature communications High 32770009
2021 IP3R1 silencing in myocardial ischemia/reperfusion injury reduces Ca2+ overload, inflammation, and pyroptosis. ERP44 binding to IP3R1 inhibits Ca2+ overload and alleviates cardiomyocyte pyroptosis. The increase in intracellular Ca2+ via IP3R1 activates the NLRP3/Caspase-1 pyroptosis pathway; NLRP3 activation reverses the protective effects of IP3R1 inhibition or ERP44 overexpression. IP3R1 siRNA in MI/R rat model and H/R cardiomyocytes, ERP44 overexpression, NLRP3 pharmacological activation, Ca2+ level measurement, pyroptosis markers Cell death discovery Medium 33568649
2021 Src kinase phosphorylates IP3R1 at Tyr353 in palmitic acid-treated hepatocytes, increasing IP3R1 protein stability (without increasing mRNA). Src inhibition (SU6656) reduces Tyr353 phosphorylation of IP3R1, decreases its protein stability, and improves mitochondrial function and reduces apoptosis. Site-specific phosphorylation detection (Tyr353 IP3R1), Src kinase inhibitor (SU6656), siRNA knockdown, protein stability assays, mitochondrial function and apoptosis measurements Experimental cell research Medium 33358861
2022 The IP3R1-GRP75-VDAC1 complex mediates Ca2+ transport from the ER to mitochondria; GRP75 deficiency (siRNA or conditional KO) impairs ER-to-mitochondria Ca2+ transport and alleviates mitochondrial oxidative stress, calcium overload, and atrial remodeling in diabetic models. In situ proximity ligation assay (IP3R1-GRP75-VDAC1 complex), mass spectrometry, GRP75 siRNA in HL-1 cells, Myh6-Cre/Hspa9-flox conditional KO mice, Ca2+ imaging Redox biology High 35344886
2023 IP3R1 underlies diastolic Ca2+ transients that activate ANO1 (Ca2+-activated Cl− channel) during diastole in lymphatic muscle cells, driving pacemaker depolarization and pressure-dependent chronotropy of lymphatic collecting vessels. Smooth muscle-specific Itpr1 KO eliminates diastolic subcellular Ca2+ transients, reduces contraction frequency, and abolishes pressure-dependent frequency modulation. Smooth muscle-specific conditional Itpr1 KO (Myh11-CreERT2), pressure myography, GCaMP6f Ca2+ imaging, membrane potential recordings in ex vivo pressurized lymphatic vessels The Journal of general physiology High 37851027
2011 shRNA-mediated knockdown of IP3R1 reduces aggregation of mutant huntingtin (polyQ) in cells; this effect of IP3R1 inhibition on aggregation does not correlate with store-operated Ca2+ entry but weakly correlates with inhibition of IP3-induced Ca2+ release, indicating a functional (rather than purely structural) contribution of IP3R1 activity to polyQ aggregation. shRNA knockdown of IP3R1, mutant huntingtin aggregation assay, comparison of 2-APB analogs on IICR vs. SOCE vs. aggregation Biochemical and biophysical research communications Low 22056561
2011 ERp44 inhibits IP3R1-mediated Ca2+ release (IICR) by binding to the L3V domain of IP3R1; ERp44 C160S/C212S mutants bind more tightly to IP3R1 but exhibit weaker inhibition of channel activity, dissociating binding affinity from functional inhibition. Pull-down assay (ERp44-IP3R1 L3V domain), Ca2+ imaging in ERp44-overexpressing HeLa cells, mutagenesis of ERp44 cysteine residues Protein & cell Medium 22183808
2018 Deletion of IP3R1 by Pdgfrb-Cre in smooth muscle cells, enteric neurons, and interstitial cells of Cajal results in impaired GI motility (prolonged gut transit, reduced spontaneous contraction frequency, reduced contractile response to carbachol and electrical field stimulation) and lethality by 40 weeks, demonstrating IP3R1 is required for normal GI tract contractility. Pdgfrb-Cre conditional IP3R1 KO mouse, cell lineage tracing, isometric tension recording, pharmacological challenges (carbachol, KCl, electrical field stimulation) Journal of gastroenterology High 30382364

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS genetics 233 17590087
1993 Widespread expression of inositol 1,4,5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system. Receptors & channels 198 8081710
2020 Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis. Nature 156 32132708
2022 IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling. Redox biology 132 35344886
2012 Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet journal of rare diseases 117 22986007
2016 Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome. American journal of human genetics 113 27108797
1994 Human inositol 1,4,5-trisphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization. The Biochemical journal 108 7945203
2008 Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology 107 18579805
2019 Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer. Molecular cancer 105 30999914
2014 ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy. Cancer research 105 25297632
2006 Phosphorylation of IP3R1 and the regulation of [Ca2+]i responses at fertilization: a role for the MAP kinase pathway. Development (Cambridge, England) 89 17038520
2016 A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect. American journal of human genetics 80 27108798
2015 'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII. Journal of neuroinflammation 77 26377085
2021 IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury. Cell death discovery 70 33568649
2010 Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends in neurosciences 67 20226542
2008 Genotypic detection of acyclovir-resistant HSV-1: characterization of 67 ACV-sensitive and 14 ACV-resistant viruses. Antiviral research 64 18336925
2004 Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology 63 15623688
2005 Inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1) modulates the acquisition of cisplatin resistance in bladder cancer cell lines. Oncogene 62 15608674
2016 Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS. Proceedings of the National Academy of Sciences of the United States of America 60 27402766
2011 SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. Archives of neurology 53 21555639
2003 Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant. Neurobiology of disease 52 12828938
2019 Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection. Viruses 51 31121928
2017 Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia. Orphanet journal of rare diseases 49 28659154
2015 Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nature neuroscience 49 25821909
1996 Anticoagulant response to Agkistrodon contortrix venom (ACV test): a new global test to screen for defects in the anticoagulant protein C pathway. Thrombosis and haemostasis 49 8743179
1991 Isolation and partial characterisation of ACV synthetase from Cephalosporium acremonium and Streptomyces clavuligerus. Evidence for the presence of phosphopantothenate in ACV synthetase. The Journal of antibiotics 48 2010361
1986 RCH-ACV: a lymphoblastic leukemia cell line with chromosome translocation 1;19 and trisomy 8. Cancer genetics and cytogenetics 48 3455845
2013 IP3R1 deficiency in the cerebellum/brainstem causes basal ganglia-independent dystonia by triggering tonic Purkinje cell firings in mice. Frontiers in neural circuits 47 24109434
2010 An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description. Movement disorders : official journal of the Movement Disorder Society 45 20669319
2018 Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development. Current neuropharmacology 44 28554312
2014 Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia. Journal of neuroinflammation 41 25498830
2015 Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PloS one 37 25734498
2004 Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus. Neurology 36 14981189
2020 Epsin-mediated degradation of IP3R1 fuels atherosclerosis. Nature communications 35 32770009
2019 GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells. Scientific reports 35 31664108
2016 A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: Expanding the phenotype of ITPR1-related spinocerebellar ataxia's. American journal of medical genetics. Part A 35 27862915
2002 Genotypic and phenotypic characterization of the thymidine kinase of ACV-resistant HSV-1 derived from an acyclovir-sensitive herpes simplex virus type 1 strain. Antiviral research 35 12406508
1992 ACV synthetase. Critical reviews in biotechnology 35 1633622
2015 The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing. Autophagy 34 25714778
2010 Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15. Cerebellum (London, England) 34 20082166
2009 Heterologous production of non-ribosomal peptide LLD-ACV in Saccharomyces cerevisiae. Metabolic engineering 32 19686863
2016 Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Clinical genetics 31 27062503
2011 Skeletal muscle IP3R1 receptors amplify physiological and pathological synaptic calcium signals. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 22031873
1990 Gene disruption of the pcbAB gene encoding ACV synthetase in Cephalosporium acremonium. Current genetics 31 2076552
2017 A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns. Journal of neurology 30 28620721
2011 Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) has InsP(3)-independent gating and disrupts intracellular Ca(2+) homeostasis. The Journal of biological chemistry 30 21859719
1996 Chronic ethanol on mRNA levels of IP3R1, IP3 3-kinase and mGluR1 in mouse Purkinje neurons. Neuroreport 30 8930970
2013 Nuclear ALG-2 protein interacts with Ca2+ homeostasis endoplasmic reticulum protein (CHERP) Ca2+-dependently and participates in regulation of alternative splicing of inositol trisphosphate receptor type 1 (IP3R1) pre-mRNA. The Journal of biological chemistry 28 24078636
2017 Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome. Gene 27 28698159
2022 A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling. Molecular psychiatry 26 35388181
2017 A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers. European journal of human genetics : EJHG 26 28488678
1999 Development of Purkinje cells in humans: an immunohistochemical study using a monoclonal antibody against the inositol 1,4,5-triphosphate type 1 receptor (IP3R1). Acta neuropathologica 25 10483778
2011 Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family. Biochemical and biophysical research communications 24 21689634
2021 Overexpression of lncRNA SLC26A4-AS1 inhibits papillary thyroid carcinoma progression through recruiting ETS1 to promote ITPR1-mediated autophagy. Journal of cellular and molecular medicine 23 34378314
2014 Ellagitannins as synergists of ACV on the replication of ACV-resistant strains of HSV 1 and 2. Antiviral research 23 25111906
2014 Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1. Mammalian genome : official journal of the International Mammalian Genome Society 23 25354648
2010 Expression of the IP3R1 promoter-driven nls-lacZ transgene in Purkinje cell parasagittal arrays of developing mouse cerebellum. Journal of neuroscience research 23 20632399
1994 Possible involvement of the lysine epsilon-aminotransferase gene (lat) in the expression of the genes encoding ACV synthetase (pcbAB) and isopenicillin N synthase (pcbC) in Streptomyces clavuligerus. Microbiology (Reading, England) 23 7881554
1999 Metabolic control analysis of the penicillin biosynthetic pathway: the influence of the LLD-ACV:bisACV ratio on the flux control. Antonie van Leeuwenhoek 22 10422587
2002 Bone marrow transplantation in a child with Wiskott-Aldrich syndrome latently infected with acyclovir-resistant (ACV(r)) herpes simplex virus type 1: emergence of foscarnet-resistant virus originating from the ACV(r) virus. Journal of medical virology 21 12210436
2016 ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia. Cerebellum & ataxias 20 26770814
2022 Decreased GZMB, NRP1, ITPR1, and SERPINB9 Transcripts Lead to Reduced Regulatory T Cells Suppressive Capacity in Generalized Vitiligo Patients. Journal of immunology research 19 36157881
2017 PLSCR1/IP3R1/Ca2+ axis contributes to differentiation of primary AML cells induced by wogonoside. Cell death & disease 19 28492556
2012 A vacuolar membrane protein affects drastically the biosynthesis of the ACV tripeptide and the beta-lactam pathway of Penicillium chrysogenum. Applied microbiology and biotechnology 19 22777282
2023 ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade. Cancer letters 18 37820992
2019 Characterization of NCS1-InsP3R1 interaction and its functional significance. The Journal of biological chemistry 18 31659121
2024 Human salivary histatin 1 regulating IP3R1/GRP75/VDAC1 mediated mitochondrial-associated endoplasmic reticulum membranes (MAMs) inhibits cell senescence for diabetic wound repair. Free radical biology & medicine 17 39343182
2017 Missense mutation in the ITPR1 gene presenting with ataxic cerebral palsy: Description of an affected family and literature review. Neurologia i neurochirurgia polska 17 28826917
2008 An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown. Neuropharmacology 17 18708078
1998 Changes in IP3R1 and SERCA2b mRNA levels in the gerbil brain after chronic ethanol administration and transient cerebral ischemia-reperfusion. Brain research. Molecular brain research 17 9602035
2022 Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature. Journal of neuroinflammation 16 35907972
2020 Atm deficiency in the DNA polymerase β null cerebellum results in cerebellar ataxia and Itpr1 reduction associated with alteration of cytosine methylation. Nucleic acids research 16 32123907
2016 GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC genomics 16 27039371
2015 HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis. Oncoimmunology 16 25949883
1989 Phosphate regulation of ACV synthetase and cephalosporin biosynthesis in Streptomyces clavuligerus. FEMS microbiology letters 16 2721913
2023 IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels. The Journal of general physiology 15 37851027
2022 Silica nanoparticles induce ovarian granulosa cell apoptosis via activation of the PERK-ATF4-CHOP-ERO1α pathway-mediated IP3R1-dependent calcium mobilization. Cell biology and toxicology 15 36346508
2021 ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum. Frontiers in genetics 15 33747042
2018 Curcumin may serve an anticancer role in human osteosarcoma cell line U-2 OS by targeting ITPR1. Oncology letters 15 29552196
2017 Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias. PloS one 15 29186133
2011 Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation. Biochemical and biophysical research communications 15 22056561
2023 Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design. Movement disorders : official journal of the Movement Disorder Society 14 37964426
2021 Paraneoplastic encephalomyeloradiculits with multiple autoantibodies against ITPR-1, GFAP and MOG: case report and literature review. Neurological research and practice 14 34635185
2019 ORP4L couples IP3 to ITPR1 in control of endoplasmic reticulum calcium release. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 31648575
2019 Stingless Bee Honey Improves Spatial Memory in Mice, Probably Associated with Brain-Derived Neurotrophic Factor (BDNF) and Inositol 1,4,5-Triphosphate Receptor Type 1 (Itpr1) Genes. Evidence-based complementary and alternative medicine : eCAM 14 31885664
2018 Deletion of IP3R1 by Pdgfrb-Cre in mice results in intestinal pseudo-obstruction and lethality. Journal of gastroenterology 14 30382364
1998 Effects of ischemic tolerance on mRNA levels of IP3R1, beta-actin, and neuron-specific enolase in hippocampal CA1 area of the gerbil brain. Neurochemical research 14 9566589
2021 Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes. Experimental cell research 13 33358861
2008 Effects of siRNA knock-down of TRPC6 and InsP(3)R1 in vasopressin-induced Ca(2+) oscillations of A7r5 vascular smooth muscle cells. Pharmacological research 13 18835357
2005 Recombinant interleukin-2 enhanced the antitumor effect of ADV/RSV-HSV-tk/ACV therapy in a murine bladder cancer model. Anticancer research 13 16080522
1995 Inhibitory action of acyclovir (ACV) and penciclovir (PCV) on plaque formation and partial cross-resistance of ACV-resistant varicella-zoster virus to PCV. Antiviral research 13 8540749
2022 Regulation of Hepatic Lipid and Glucose Metabolism by INSP3R1. Diabetes 12 35657697
2022 Superior Cerebellar Atrophy: An Imaging Clue to Diagnose ITPR1-Related Disorders. International journal of molecular sciences 12 35743164
2021 A novel de novo intronic variant in ITPR1 causes Gillespie syndrome. American journal of medical genetics. Part A 12 33949769
2018 Identification of a Splicing Mutation in ITPR1 via WES in a Chinese Early-Onset Spinocerebellar Ataxia Family. Cerebellum (London, England) 12 29196976
2012 Regulation of inositol 1,4,5-triphosphate receptor, type 1 (IP3R1) in hypoxic/reperfusion injury of white matter. Neurological research 12 22643045
2011 ERp44 C160S/C212S mutants regulate IP3R1 channel activity. Protein & cell 12 22183808
2010 Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series. Movement disorders : official journal of the Movement Disorder Society 12 20437544
1997 ACV synthetase: expression of amino acid activating domains of the Penicillium chrysogenum enzyme in Aspergillus nidulans. Biochemical and biophysical research communications 12 9266851
1997 Penicillin biosynthesis: intermediates of biosynthesis of delta-L-alpha-aminoadipyl-L-cysteinyl-D-valine formed by ACV synthetase from Acremonium chrysogenum. FEBS letters 12 9305735

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