Calsequestrin-2 is an acidic calcium-storage protein of the cardiac sarcoplasmic reticulum. Calcium-dependent assembly into oligomers and polymers supports its high-capacity buffering of luminal calcium. Association with the ryanodine-receptor release complex couples this reservoir to regulated calcium release for cardiac contraction. CASQ2 variants can disturb calcium storage, polymerization or release-complex regulation. Biallelic pathogenic variants and certain heterozygous variants cause catecholaminergic polymorphic ventricular tachycardia, with variant-dependent mechanisms and penetrance. The protein supplies calcium buffering and regulatory interactions; the ryanodine receptor supplies the ion-conducting pore.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002027 regulation of heart rate | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CASQ2 calcium handling influences cardiac rhythm. Reason: The mouse-ortholog transfer is consistent with human CASQ2-associated tachyarrhythmia and target-protein effects on SR calcium storage and release. Retain this broad rhythm outcome as non-core; the mechanistic core is luminal calcium sequestration and release regulation, rather than an asserted pacemaker-specific activity. The original mouse donor experiment was not independently reconstructed. |
| GO:0002027 regulation of heart rate | IMP PMID:15485681 Calsequestrin mutant D307H exhibits depressed binding to its... | KEEP AS NON CORE | Summary: The D307H study supports arrhythmia-related CASQ2 dysfunction. Reason: The complete primary abstract describes human wild-type and D307H CASQ2, altered calcium responsiveness and reduced interactions with triadin/junctin. These changes fit the well-supported rhythm phenotype. Retain the curator-supported broad outcome while making no claim that the accessible abstract directly measured heart rate or established a pacemaker mechanism. |
| GO:0002027 regulation of heart rate | IMP PMID:16601229 Abnormal interactions of calsequestrin with the ryanodine re... | KEEP AS NON CORE | Summary: CASQ2-dependent release regulation influences rhythm. Reason: Human R33Q genetics and expression in adult rat myocytes connect altered CASQ2 regulation to spontaneous calcium waves and sparks; planar-bilayer assays distinguish wild-type from mutant inhibition of RyR2. The clinical rhythm outcome is retained as non-core alongside this direct calcium-handling mechanism. Native human pacemaker physiology was not assayed in the accessible abstract. Supporting Evidence: |
| GO:0002027 regulation of heart rate | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | KEEP AS NON CORE | Summary: CASQ2 mutation-associated calcium dysregulation contributes to tachyarrhythmia. Reason: The source combines human patient genetics with recombinant protein and rat-myocyte experiments, including delayed afterdepolarizations under isoproterenol. This supports the broad rhythm annotation with curator deference, without equating tachyarrhythmia with a dedicated basal heart-rate-setting mechanism. Supporting Evidence: |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium binding is fundamental to CASQ2 storage activity. Reason: The PAINT calcium-binding assertion agrees with multiple direct human protein assays. The target in WITH/FROM is legitimate descendant evidence, not circularity. The family tree and placement at PTN000004016 were not independently inspected; no node-placement defect is asserted. The more informative sequestering activity is already present elsewhere in this source set. |
| GO:0005509 calcium ion binding | IDA PMID:16601229 Abnormal interactions of calsequestrin with the ryanodine re... | ACCEPT | Summary: Wild-type CASQ2 binds calcium. Reason: The primary abstract directly reports comparable calcium-binding capacities of recombinant wild-type and R33Q CASQ2 under the tested conditions. Its separate bilayer defect shows why preserved bulk binding does not establish preserved release regulation. Retain this direct molecular property, without imposing another paper's mutant-binding result on these conditions. Supporting Evidence: |
| GO:0005509 calcium ion binding | IDA PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: CASQ2 has experimentally measured calcium-binding activity. Reason: The source compares recombinant human disease variants: the truncation fails to bind calcium, whereas L167H has normal binding in the reported assay. The comparison directly supports the wild-type activity. It does not establish that all pathogenic variants reduce binding under every assay condition. Supporting Evidence: |
| GO:0005509 calcium ion binding | IDA PMID:17881003 Characterization of human cardiac calsequestrin and its dele... | ACCEPT | Summary: Human CASQ2 binds calcium with high capacity. Reason: Human wild-type structural and biochemical experiments link calcium binding to polymerization; the tested R33Q, L167H and D307H mutants show reduced binding in this study. Earlier reports of preserved capacity for particular mutants remain assay-dependent observations, not evidence that this reference is miscited. Supporting Evidence: |
| GO:0005509 calcium ion binding | IDA PMID:21416293 Phosphorylation of human calsequestrin: implications for cal... | ACCEPT | Summary: Human CASQ2 calcium binding responds to C-terminal modification. Reason: The source identifies human CASQ2 phosphorylation sites and measures binding by phosphomimetic mutants. The double substitution increases binding above 6 mM calcium; neither single substitution produces the same effect. This is direct binding evidence, not proof that all proposed trafficking effects were experimentally measured. Supporting Evidence: |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: The domain-based calcium-binding assignment is corroborated experimentally. Reason: The exact InterPro identifiers are retained. Independent human CASQ2 biochemical studies establish calcium binding, so retention does not rest on the sequence signatures alone or attribute an unmeasured catalytic activity. |
| GO:0005513 detection of calcium ion | TAS PMID:22123818 Role of Junctin protein interactions in cellular dynamics of... | ACCEPT | Summary: CASQ2 converts calcium changes into altered polymer state. Reason: The term concerns reception of calcium stimulus and conversion into a molecular signal. Live-cell and purified-protein experiments show calcium-dependent CASQ2 polymer changes coupled to junctin interactions, providing a molecular calcium-responsive mechanism. This supports the existing sensing annotation; it does not imply a transmembrane calcium-sensor receptor or an independently measured downstream signaling pathway in every preparation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22123818 Role of Junctin protein interactions in cellular dynamics of... | KEEP AS NON CORE | Summary: CASQ2 associates with junctin in a defined heterologous system. Reason: Human CSQ2 and mouse junctin were coexpressed in murine C2C12 cells. Reciprocal coimmunoprecipitation and acceptor-photobleaching FRET support their association, which persists after thapsigargin-induced calcium depletion. The paper explicitly distinguishes constant CSQ2–junctin interaction from calcium-dependent polymer disassembly, so these assays do not justify replacing this exact partner edge with calcium-dependent protein binding. Retain the Q8BSY0 association as non-core under the explicit supported-binding instruction in projects/CLINGEN_MENDELIAN.md, Curation instructions; no purified binary interface or additional molecular activity is inferred. Supporting Evidence: PMID:22123818 constant interactions between CSQ2 and JNT, regardless of the SR Ca(2+) concentration |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The curated CASQ2–BYSL interaction is retained with limited scope. Reason: The original HuRI IPI assertion and exact Q13895 partner agree with the immutable reviewed UniProt interaction record. Retain the qualitative edge with curator deference under the explicit supported-binding instruction in projects/CLINGEN_MENDELIAN.md, Curation instructions. The normal SR-luminal and nucleolar contexts constrain a native physiological interpretation, but do not contradict the curated heterologous interaction assay. Individual target-table entries and controls were not independently authenticated, and no shared native compartment, BYSL ribosome-related function or more specific CASQ2 molecular activity is inferred. |
| GO:0005737 cytoplasm | IDA PMID:22123818 Role of Junctin protein interactions in cellular dynamics of... | KEEP AS NON CORE | Summary: The broad cytoplasmic location is supported but adds no specific core compartment. Reason: The primary Results place tagged human CSQ2 speckles within the cytoplasmic region of transfected mouse C2C12 cells. Cytoplasm includes organelles and is not soluble cytosol. Retain this correct broad location as non-core because the functional synthesis identifies the more informative sarcoplasmic-reticulum lumen. Recognizing the cytoplasmic region does not resolve whether a signal lies within a Z-disc or adjacent junctional SR; the separate Z-disc uncertainties therefore remain. The experiment is not endogenous human-cardiomyocyte imaging or lumen-marker colocalization. Supporting Evidence: |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: CASQ2 acts in the specialized endoplasmic reticulum of muscle. Reason: Sarcoplasmic reticulum is specialized endoplasmic reticulum, and independent target biochemistry supports luminal calcium storage there. Retain the broad PAINT location; its exact ancestral node and donor alignment were not inspected. The core uses the independently supported, more precise SR lumen. |
| GO:0006874 intracellular calcium ion homeostasis | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: CASQ2 directly buffers intracellular calcium stores. Reason: The study measures altered calcium storage and release in rat myocytes expressing human disease variants, together with recombinant binding effects. Calcium sequestration is CASQ2's own contribution to homeostasis, rather than a process inferred only from clinical necessity. Supporting Evidence: |
| GO:0006941 striated muscle contraction | TAS PMID:9795116 Cloning of the genes encoding mouse cardiac and skeletal cal... | KEEP AS NON CORE | Summary: CASQ2 supports contraction through calcium storage and release. Reason: The cited abstract concerns mouse cDNA cloning and rodent embryonic expression, not a directly visible human contractility assay. Independent human target-protein perturbations support the broad striated-muscle context through calcium availability. Retain the existing TAS as a non-core outcome; no direct force-generating or myofilament activity is assigned to CASQ2. |
| GO:0010649 regulation of cell communication by electrical coupling | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | UNDECIDED | Summary: The specific intercellular electrical-coupling assignment remains unresolved. Reason: GO:0010649 concerns cell communication by electrical coupling, including current flow between adjacent cells; it is distinct from excitation–contraction coupling inside one myocyte. The accessible original abstract establishes intracellular calcium changes and delayed afterdepolarizations, but the complete original experiments could not be accessed after publisher and repository attempts. Preserve uncertainty about the specific intercellular claim; do not remove an experimental annotation merely because it is absent from the abstract. Supporting Evidence: |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: CASQ2 regulates release from the sarcoplasmic reticulum. Reason: The exact mouse orthology source is preserved. Independent human CASQ2 experiments in rat myocytes and reconstituted channel preparations establish effects on SR release, so the existing broad conserved process is supported without claiming inspection of every mouse donor experiment. |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: CASQ2 participates in controlling SR calcium release. Reason: The original ortholog accession P12637 is preserved, with its original assay not independently reconstructed. Human target-protein biochemical and myocyte evidence independently corroborates this conserved process. CASQ2 supplies buffering and release-complex regulation, rather than the conducting pore. |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | IBA GO_REF:0000033 | ACCEPT | Summary: CASQ2 calcium handling regulates cardiac contraction. Reason: The PAINT inference is consistent with human CASQ2 perturbations that change stored calcium and evoked release in rat cardiomyocytes. Retain the inherited process on that independent target evidence; the target in WITH/FROM is valid descendant grounding. PTN002559177 placement has not been inspected and is not declared defective. |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | IDA PMID:16601229 Abnormal interactions of calsequestrin with the ryanodine re... | ACCEPT | Summary: CASQ2 regulates the release component of cardiac excitation–contraction coupling. Reason: The source reports recombinant wild-type inhibition of RyR2 at low luminal calcium in planar bilayers and altered coupling gain after human R33Q expression in adult rat myocytes. This is direct regulatory work by CASQ2; the abstract does not specify every protein construct or bilayer component, so no purified-pair-only or wholly human preparation is claimed. Supporting Evidence: |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | IMP PMID:16601229 Abnormal interactions of calsequestrin with the ryanodine re... | ACCEPT | Summary: Perturbing CASQ2 alters calcium release supporting contraction. Reason: The human R33Q protein produces more spontaneous calcium events and altered excitation–contraction gain in adult rat cardiomyocytes compared with wild type. These measurements support the existing cardiac release-regulation process, without treating the rat cell experiments as native human tissue measurements. Supporting Evidence: |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: Human CASQ2 variants alter calcium available for cardiac contraction. Reason: Recombinant binding assays and expression of human variants in rat myocytes demonstrate reduced SR calcium storage and evoked release. The process reflects CASQ2's buffering/regulatory work, not merely its association with disease. The two mutant mechanisms are distinguished in the source. Supporting Evidence: |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | ISS GO_REF:0000024 | ACCEPT | Summary: The orthology-based cardiac calcium-release role is corroborated in human protein studies. Reason: Preserve P12637 and the manual transfer source without asserting inspection of the original donor assay. Human CASQ2 perturbation and biochemical evidence independently supports this existing process, including regulation at the SR release complex. |
| GO:0014701 junctional sarcoplasmic reticulum membrane | TAS PMID:17569730 Protein protein interactions between triadin and calsequestr... | ACCEPT | Summary: CASQ2 associates with the luminal face of junctional SR release units. Reason: The original study disrupts the triadin–CASQ2 interaction using a luminal triadin peptide in rat ventricular myocytes and channel preparations. Together with target complex evidence, this supports peripheral association at junctional SR membrane. The annotation does not mean CASQ2 is an integral membrane-spanning protein, and the accessible cache is abstract-only. |
| GO:0014802 terminal cisterna | IBA GO_REF:0000033 | ACCEPT | Summary: The junctional SR reservoir is a core CASQ2 location. Reason: The terminal-cisterna PAINT inference is consistent with localization of CASQ2 to the luminal reservoir at calcium-release units. Retain the conserved compartment while disclosing that the PTN000004019 placement and individual donor preparations were not inspected. No skeletal-muscle-specific cisternal geometry is asserted for every cardiac preparation. |
| GO:0016529 sarcoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: CASQ2 is a sarcoplasmic-reticulum calcium-storage protein. Reason: The broad SR location transferred from P12637 is independently supported by human CASQ2 biochemical studies and the curated human release complex. The original donor accession remains unchanged; target corroboration does not pretend to revalidate the original donor microscopy. |
| GO:0030018 Z disc | IBA GO_REF:0000033 | UNDECIDED | Summary: The Z-disc-specific PAINT location needs resolved compartment evidence. Reason: CASQ2 storage in nearby junctional SR does not alone establish membership of the sarcomeric Z disc. Experimental mouse/rat Z-disc annotations are present in the dated comparative GO graph, so the inference is not rejected from sequence or donor count. The relevant imaging and PTN000004019 placement have not been inspected; whether the signal identifies Z-disc material or adjacent SR remains unresolved. |
| GO:0030018 Z disc | IEA GO_REF:0000107 | UNDECIDED | Summary: The precise transferred Z-disc localization is not yet resolved. Reason: The mouse orthology source is retained. A dated MGI graph points to mouse experimental localization, but its primary images and spatial resolution were not read. CASQ2's established SR location does not by itself contradict a spatially related Z-disc annotation or prove it; retain uncertainty rather than infer an electronic error. |
| GO:0030018 Z disc | ISS GO_REF:0000024 | UNDECIDED | Summary: The P51868-derived Z-disc assignment needs source-specific localization evidence. Reason: The exact donor accession and manual ortholog transfer are preserved. The dated comparative graph includes rat experimental Z-disc evidence, but the original assay and relationship of labeling to the SR versus sarcomere were not independently inspected. No wrong-ortholog or compartment error is asserted from unavailable full evidence. |
| GO:0030314 junctional membrane complex | IEA GO_REF:0000107 | ACCEPT | Summary: CASQ2 participates in the junctional calcium-release complex. Reason: The transferred mouse annotation is corroborated by CASQ2 association with triadin/junctin and the RyR release unit. This supports a component of the junctional membrane complex, with CASQ2 positioned on its luminal side. It does not imply membrane insertion or formation of the intermembrane junction by CASQ2 alone. |
| GO:0033017 sarcoplasmic reticulum membrane | IEA GO_REF:0000117 | ACCEPT | Summary: CASQ2 is associated with the SR membrane through release-complex proteins. Reason: The ARBA prediction is supported by the established peripheral luminal association of CASQ2 with anchoring proteins. A membrane location includes peripheral association; no transmembrane helix or ion channel activity is inferred. The core identifies the lumen where sequestration occurs. |
| GO:0033017 sarcoplasmic reticulum membrane | TAS Reactome:R-HSA-2855020 | ACCEPT | Summary: The curated release complex supports peripheral SR-membrane association. Reason: The Reactome summary explicitly assigns CASQ2 calcium buffering and association through triadin/junctin within the SR release complex. The event compartment is interpreted together with this molecular association, rather than as proof that CASQ2 transports ions across the membrane. Supporting Evidence: Reactome:R-HSA-2855020 |
| GO:0033018 sarcoplasmic reticulum lumen | IBA GO_REF:0000033 | ACCEPT | Summary: CASQ2 sequesters calcium in the SR lumen. Reason: The PAINT compartment agrees with target biochemical and release-complex evidence. Preserve the donor set and PTN000004019 without inventing a node-placement audit. The lumen is the calcium reservoir enclosed by the SR membrane; it is distinct from free cytosol. |
| GO:0033018 sarcoplasmic reticulum lumen | IC PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: The inferred SR-lumen compartment is independently consistent with CASQ2 biology. Reason: The original IC cites the release-regulation annotation. Luminal calcium storage and the experimental sensitivity of release to CASQ2 variants provide additional, independent context for the location. Retention does not claim that the clinical study performed direct human ultrastructural localization. |
| GO:0033018 sarcoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: CASQ2 is a luminal SR buffer. Reason: The combined mouse-orthology and UniProt location mapping is corroborated by the target's calcium-storage role and release-complex organization. Preserve both source components; this is a luminal assignment, not inference of soluble cytosolic localization. |
| GO:0034704 calcium channel complex | TAS PMID:19403607 Junctin and the histidine-rich Ca2+ binding protein: potenti... | ACCEPT | Summary: CASQ2 is an accessory component of the calcium-release channel complex. Reason: The cited review explicitly includes calsequestrin with RyR, junctin and triadin in the SR calcium-release unit. Primary target interaction and modulation studies corroborate that organization. Membership of a channel complex does not assign the pore's calcium-channel activity to every component. |
| GO:0043267 negative regulation of potassium ion transport | IEA GO_REF:0000107 | UNDECIDED | Summary: The transferred direction of potassium-transport regulation requires the original assay details. Reason: The mouse orthology chain is preserved; the dated MGI graph links the corresponding mouse experimental assertion to the hERG study. Its accessible abstract reports differential modulation in Xenopus oocytes but does not expose the complete direction, construct and condition comparisons. Full text could not be accessed. Keep the specific negative effect unresolved rather than infer a universal inhibition from broad CASQ2 calcium-buffering activity. Supporting Evidence: |
| GO:0043267 negative regulation of potassium ion transport | ISS PMID:21063088 Modulation of human ether a gogo related channels by CASQ2 c... | UNDECIDED | Summary: The specific negative potassium-transport transfer remains access-limited. Reason: The cited study directly examines hERG currents in Xenopus oocytes, and the source preserves mouse O09161. The complete paper and relevant wild-type/mutant direction controls were inaccessible. The abstract supports modulation but cannot by itself settle the exact negative term; neither wrong species nor absence of any effect is alleged. Supporting Evidence: |
| GO:0045214 sarcomere organization | IEA GO_REF:0000107 | UNDECIDED | Summary: A direct sarcomere-organization role is unresolved. Reason: The mouse transfer is grounded in an experimental donor annotation in the dated comparative GO graph, not merely a gene label. The primary perturbation and structural measurements were not inspected. Altered calcium handling may secondarily remodel sarcomeres, but that possibility alone neither verifies nor disproves the existing participation claim. Preserve uncertainty pending the actual donor mechanism. |
| GO:0048306 calcium-dependent protein binding | IDA PMID:15485681 Calsequestrin mutant D307H exhibits depressed binding to its... | ACCEPT | Summary: CASQ2 binds release-complex partners in a calcium-dependent manner. Reason: The source directly reports altered calcium-dependent binding of human D307H CASQ2 to triadin and junctin relative to wild type. This is a specific calcium-sensitive interaction property central to the release unit, rather than an uninformative partner-function transfer. No new binding-interface residues or universal dissociation threshold are asserted. Supporting Evidence: |
| GO:0051258 protein polymerization | IDA PMID:17881003 Characterization of human cardiac calsequestrin and its dele... | ACCEPT | Summary: CASQ2 assembles into calcium-dependent polymers. Reason: Human wild-type and mutant light-scattering experiments link polymerization behavior to high-capacity calcium binding. CASQ2 itself forms the assembly, so this existing process is supported by physical participation rather than necessity alone. Native polymer geometry is not inferred from the abstract. Supporting Evidence: |
| GO:0051258 protein polymerization | IDA PMID:22123818 Role of Junctin protein interactions in cellular dynamics of... | ACCEPT | Summary: CASQ2 polymer state responds to calcium perturbation. Reason: The primary study combines live-cell polymer observations with purified-protein microscopy; junctin facilitates decondensation as calcium changes. CASQ2 is the assembling protein. Human CSQ2 in mouse cells and purified preparations must not be conflated with an endogenous human cardiac imaging assay. Supporting Evidence: |
| GO:0051258 protein polymerization | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA polymerization assignment has direct target corroboration. Reason: Human CASQ2 biochemical polymerization experiments independently support the broad process predicted by ARBA. The source rule is preserved; its individual rule logic was not inspected. |
| GO:0051279 regulation of release of sequestered calcium ion into cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: CASQ2 regulates release of stored calcium into cytosol. Reason: Independent human CASQ2 protein studies show effects on SR release and channel-complex regulation, corroborating this broad automated process assertion. The more specific cardiac SR process is represented in existing annotations and the core; an extra redundant annotation is unnecessary. |
| GO:0060048 cardiac muscle contraction | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: CASQ2 calcium storage contributes to cardiac contraction. Reason: Human variant expression changes the calcium reservoir and evoked release in rat cardiomyocytes. Buffering the calcium subsequently released for contraction is CASQ2's own physiological contribution. The accessible abstract does not imply that CASQ2 is a contractile motor or that native human force was directly measured. Supporting Evidence: |
| GO:0060306 regulation of membrane repolarization | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific repolarization transfer requires fuller donor evidence. Reason: The source is a mouse orthology inference. The linked hERG literature establishes heterologous channel modulation, but the complete assay conditions, direction controls and connection to a repolarization endpoint were not read. Preserve uncertainty for this process-specific transfer, while accepting CASQ2's independent SR calcium-buffering function. Supporting Evidence: |
| GO:0060306 regulation of membrane repolarization | ISS PMID:21063088 Modulation of human ether a gogo related channels by CASQ2 c... | UNDECIDED | Summary: The repolarization inference is plausible but not fully verified. Reason: The original study tests hERG currents in Xenopus oocytes and discusses repolarizing potassium currents. The cache is abstract-only and live full-text access failed. Preserve mouse O09161 and the existing ISS assertion as unresolved rather than treating this preparation as a direct native human repolarization assay or declaring it wrong. Supporting Evidence: |
| GO:0071313 cellular response to caffeine | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | KEEP AS NON CORE | Summary: CASQ2 influences calcium mobilization during caffeine challenge. Reason: Retain the curator-supported experimental response as a non-core challenge context consistent with altered SR calcium stores and release. The cached abstract does not expose the caffeine protocol, and external full-text access was unsuccessful, so the particular challenge measurements were not independently revalidated. This is not a claim that CASQ2 binds or metabolizes caffeine. Supporting Evidence: |
| GO:0086029 Purkinje myocyte to ventricular cardiac muscle cell signaling | NAS PMID:22198169 Calsequestrin 2 and arrhythmias. | UNDECIDED | Summary: The precise Purkinje-to-ventricular signaling role remains unresolved. Reason: Selected complete cellular-arrhythmia prose from the cited review distinguishes RyR2-mutant conduction-system ablation from Casq2-knockout activation maps and leaves the exact cellular origin unsettled. Calcium-dependent triggered activity does not by itself resolve the specific directional transfer of information from Purkinje to ventricular cells. The uncertainty concerns this process boundary, not the NAS code or an assertion that intracellular calcium handling cannot contribute. Supporting Evidence: |
| GO:0140314 calcium ion sequestering activity | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium sequestration is the principal CASQ2 molecular activity. Reason: The PAINT assertion agrees with human protein binding-capacity measurements and variant effects on SR storage. The target in WITH/FROM is legitimate experimental grounding, not circularity. PTN000004016 placement remains uninspected, with no demonstrated propagation defect. |
| GO:0140314 calcium ion sequestering activity | IDA PMID:21416293 Phosphorylation of human calsequestrin: implications for cal... | ACCEPT | Summary: Human CASQ2 has calcium-storage capacity. Reason: The source measures human CASQ2 calcium-binding capacity and its alteration by a double phosphomimetic substitution. Together with the protein's high-capacity storage role, this supports sequestration, without claiming the source established every proposed in vivo trafficking mechanism. |
| GO:0140314 calcium ion sequestering activity | IEA GO_REF:0000107 | ACCEPT | Summary: The conserved sequestration inference is directly corroborated in human CASQ2. Reason: Retain the exact mouse orthology source. Human CASQ2 calcium-binding-capacity measurements and target-variant effects on SR storage establish the same molecular activity independently; no extra annotation is needed to restate it. |
| GO:0140314 calcium ion sequestering activity | IMP PMID:16908766 Clinical phenotype and functional characterization of CASQ2 ... | ACCEPT | Summary: CASQ2 retains calcium in the SR reservoir. Reason: Human disease variants impair SR calcium storage when expressed in rat cardiomyocytes, with recombinant binding measurements separating the mutant mechanisms. This directly supports sequestration by the wild-type protein, while preserving the human-protein/rat-cell experimental distinction. Supporting Evidence: |
| GO:1905024 regulation of membrane repolarization during ventricular cardiac muscle cell action potential | IEA GO_REF:0000107 | UNDECIDED | Summary: Ventricular action-potential repolarization is more specific than the evidence independently verified here. Reason: The mouse orthology source is preserved. The accessible hERG abstract concerns heterologous oocyte currents and a proposed cardiac consequence; the complete donor experiments needed to judge this specific ventricular phase were unavailable. No categorical denial of CASQ2 effects on repolarization is made. Supporting Evidence: |
| GO:1905024 regulation of membrane repolarization during ventricular cardiac muscle cell action potential | ISS PMID:21063088 Modulation of human ether a gogo related channels by CASQ2 c... | UNDECIDED | Summary: The ventricular-repolarization ISS assertion awaits complete source appraisal. Reason: The source and mouse O09161 donor are unchanged. Heterologous hERG modulation is relevant, but the original full paper, endpoint linkage and conditions were not read. Retain uncertainty about the specific ventricular action-potential process rather than promote an abstract-level model to an independently demonstrated human physiological result. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which original experiments support CASQ2 regulation of communication by electrical coupling between cells, separately from intracellular excitation–contraction coupling?
Q: Do mouse and rat Z-disc images place CASQ2 within sarcomeric material or adjacent junctional SR, and which evidence supports the PAINT node underlying that anatomical transfer?
Q: What direct molecular contribution to sarcomere organization underlies the mouse donor inference, rather than a secondary consequence of altered calcium cycling?
Q: Which exact CASQ2 constructs, current directions and physiological endpoint comparisons support the potassium-transport and ventricular-repolarization transfers from the hERG study?
Q: Does CASQ2 perform a specifically demonstrated step in Purkinje-to-ventricular signaling, rather than contribute more generally to triggered activity and calcium-release stability?
Q: How do the two reviewed alternative products differ in expression and calcium-storage or release-complex function, given that the available studies do not independently test both current product sequences?
Q: Which human CSQ2–RyR2 preparations distinguish direct channel modulation from changes in free luminal calcium and buffering, and how do junctin, triadin, polymer state and calcium concentration determine the direction and magnitude of regulation?
Experiment: Compare matched human CASQ2 preparations in calcium-binding, polymerization and reconstituted RyR2-release assays, controlling free luminal calcium, total calcium buffering and anchoring proteins to distinguish reservoir effects from channel-complex regulation.
Experiment: Use endogenous tagged CASQ2 and ultrastructural compartment markers in cardiomyocytes to resolve SR-lumen, peripheral-membrane and apparent Z-disc signals without relying on an overexpressed fluorescence pattern alone.
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