Calmodulin-2 is one of three mouse calmodulin genes that encode the same 149 aa calcium sensor protein. Calm2 contributes to broadly conserved calmodulin activities including calcium binding, calcium-dependent regulation of ion channels and exchangers, and activation of calmodulin-responsive kinases and phosphatases. Because Calm1, Calm2, and Calm3 encode identical proteins but differ in gene regulation, many fine-grained ISO annotations transferred from rat calmodulin paralogs are best treated as non-core or over-annotated for the Calm2 locus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization Supporting Evidence: file:mouse/Calm2/Calm2-deep-research-falcon.md Falcon synthesis supports Calm2 as a canonical four-EF-hand calcium sensor and notes that Calm1/2/3 encode identical calmodulin proteins. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization in some contexts Reason: Tissue-specific or specialized function |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Regulates RyR-mediated calcium release from SR Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | IBA GO_REF:0000033 | ACCEPT | Summary: Core calcium sensing function Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization |
| GO:0005813 centrosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Centrosomal localization for cell division Reason: Tissue-specific or specialized function |
| GO:0043209 myelin sheath | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Myelin sheath localization Reason: Tissue-specific or specialized function |
| GO:0000086 G2/M transition of mitotic cell cycle | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cell cycle regulation at G2/M transition Reason: Tissue-specific or specialized function |
| GO:0000922 spindle pole | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Spindle pole localization during mitosis Reason: Tissue-specific or specialized function |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization |
| GO:0005819 spindle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Spindle localization for cell division Reason: Tissue-specific or specialized function |
| GO:0006897 endocytosis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Endocytosis regulation Reason: Tissue-specific or specialized function |
| GO:0051649 establishment of localization in cell | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Intracellular localization establishment Reason: Tissue-specific or specialized function |
| GO:0098793 presynapse | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Presynaptic enrichment is plausible for calmodulin but represents specialized neuronal context rather than a universal Calm2 localization. Reason: Tissue-specific or specialized function |
| GO:0150034 distal axon | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Distal axon localization Reason: Tissue-specific or specialized function |
| GO:0000785 chromatin | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Chromatin association Reason: Tissue-specific or specialized function |
| GO:0001975 response to amphetamine | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Amphetamine response in neurons Reason: Tissue-specific or specialized function |
| GO:0002027 regulation of heart rate | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Heart-rate physiology is a downstream tissue-level consequence of calmodulin ion-channel regulation, not the primary molecular function of Calm2. Reason: Tissue-specific or specialized function |
| GO:0005246 calcium channel regulator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Regulates L-type calcium channels and ryanodine receptors Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | IEA GO_REF:0000120 | ACCEPT | Summary: Core calcium sensing function Reason: Core calmodulin function or localization |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear localization in some contexts Reason: Tissue-specific or specialized function |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization |
| GO:0005813 centrosome | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Centrosomal localization for cell division Reason: Tissue-specific or specialized function |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization |
| GO:0005876 spindle microtubule | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Spindle microtubule association Reason: Tissue-specific or specialized function |
| GO:0008179 adenylate cyclase binding | IEA GO_REF:0000120 | ACCEPT | Summary: Binds adenylate cyclase Reason: Core calmodulin function or localization |
| GO:0010856 adenylate cyclase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates adenylate cyclase for cAMP signaling Reason: Core calmodulin function or localization |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Regulates RyR-mediated calcium release from SR Reason: Core calmodulin function or localization |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cardiac calcium-induced calcium release is a tissue-specific physiological context downstream of calmodulin channel regulation. Reason: Tissue-specific or specialized function |
| GO:0016240 autophagosome membrane docking | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Autophagosome docking regulation Reason: Tissue-specific or specialized function |
| GO:0019855 calcium channel inhibitor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Inhibits IP3 receptors and certain calcium channels Reason: Core calmodulin function or localization |
| GO:0019901 protein kinase binding | IEA GO_REF:0000120 | ACCEPT | Summary: Binds CaMK family and other protein kinases Reason: Core calmodulin function or localization |
| GO:0019904 protein domain specific binding | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Parent binding term for diverse calmodulin-recognition motifs; too generic to capture the relevant interactions precisely. Reason: Too general - more specific terms are available |
| GO:0030017 sarcomere | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Sarcomere localization in muscle Reason: Tissue-specific or specialized function |
| GO:0030235 nitric-oxide synthase regulator activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Regulation of nitric-oxide synthases is plausible for calmodulin proteins but is better treated as specialized, non-core biology for Calm2. Reason: Tissue-specific or specialized function |
| GO:0030426 growth cone | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Neuronal growth cone localization Reason: Tissue-specific or specialized function |
| GO:0030672 synaptic vesicle membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Synaptic vesicle localization Reason: Tissue-specific or specialized function |
| GO:0031432 titin binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Titin binding in muscle Reason: Tissue-specific or specialized function |
| GO:0031800 type 3 metabotropic glutamate receptor binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: mGluR3 binding in neurons Reason: Tissue-specific or specialized function |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Mitochondrial membrane association Reason: Tissue-specific or specialized function |
| GO:0032465 regulation of cytokinesis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytokinesis regulation with CP110 and centrin Reason: Tissue-specific or specialized function |
| GO:0032991 protein-containing complex | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Too general - more specific terms available Reason: Too general - more specific terms are available |
| GO:0034704 calcium channel complex | IEA GO_REF:0000120 | ACCEPT | Summary: Component of calcium channel complexes Reason: Core calmodulin function or localization |
| GO:0035458 cellular response to interferon-beta | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Interferon-beta response Reason: Tissue-specific or specialized function |
| GO:0043209 myelin sheath | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Myelin sheath localization Reason: Tissue-specific or specialized function |
| GO:0043539 protein serine/threonine kinase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates CaMKII and other calcium-dependent kinases Reason: Core calmodulin function or localization |
| GO:0043548 phosphatidylinositol 3-kinase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PI3K binding for signaling Reason: Tissue-specific or specialized function |
| GO:0044325 transmembrane transporter binding | IEA GO_REF:0000120 | ACCEPT | Summary: Binds ion channels and transporters Reason: Core calmodulin function or localization |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: JAK-STAT pathway regulation Reason: Tissue-specific or specialized function |
| GO:0048306 calcium-dependent protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Calcium-dependent target protein binding Reason: Core calmodulin function or localization |
| GO:0050998 nitric-oxide synthase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Binding to nitric-oxide synthases is plausible but represents specialized signaling context rather than a core Calm2 function. Reason: Tissue-specific or specialized function |
| GO:0051412 response to corticosterone | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Corticosterone response Reason: Tissue-specific or specialized function |
| GO:0051592 response to calcium ion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Response to calcium ion Reason: Tissue-specific or specialized function |
| GO:0055117 regulation of cardiac muscle contraction | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cardiac contraction is a downstream tissue-level process; the direct supported function is calcium/channel regulation. Reason: Tissue-specific or specialized function |
| GO:0071346 cellular response to type II interferon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Interferon-gamma response Reason: Tissue-specific or specialized function |
| GO:0072542 protein phosphatase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates calcineurin (PP2B) phosphatase Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | IEA GO_REF:0000120 | ACCEPT | Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization |
| GO:0098685 Schaffer collateral - CA1 synapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Hippocampal synapse localization Reason: Tissue-specific or specialized function |
| GO:0098901 regulation of cardiac muscle cell action potential | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cardiac action potential regulation Reason: Tissue-specific or specialized function |
| GO:0099523 presynaptic cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Presynaptic localization Reason: Tissue-specific or specialized function |
| GO:0099524 postsynaptic cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Postsynaptic localization Reason: Tissue-specific or specialized function |
| GO:0140056 organelle localization by membrane tethering | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Organelle membrane tethering Reason: Tissue-specific or specialized function |
| GO:1900242 regulation of synaptic vesicle endocytosis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Synaptic vesicle endocytosis regulation Reason: Tissue-specific or specialized function |
| GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cardiac electrical coupling regulation Reason: Tissue-specific or specialized function |
| GO:1902494 catalytic complex | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Catalytic complex is too generic to be useful and adds no mechanistic precision beyond more specific binding and channel-complex terms. Reason: Too general - more specific terms are available |
| GO:1990456 mitochondrion-endoplasmic reticulum membrane tethering | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ER-mitochondria contact regulation Reason: Tissue-specific or specialized function |
| GO:2000300 regulation of synaptic vesicle exocytosis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Synaptic vesicle exocytosis regulation Reason: Tissue-specific or specialized function |
| GO:0060315 negative regulation of ryanodine-sensitive calcium-release channel activity | ISO GO_REF:0000119 | ACCEPT | Summary: Inhibits ryanodine receptor under certain conditions Reason: Core calmodulin function or localization |
| GO:0000785 chromatin | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Rat calmodulin paralogs all carry this chromatin term; for mouse Calm2 this is better treated as a specialized, non-core localization than a locus-defining function. Reason: Paralog-sensitive ISO transfer reflects specialized context rather than a Calm2 core role |
| GO:0000922 spindle pole | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Spindle pole localization during mitosis Reason: Tissue-specific or specialized function |
| GO:0002027 regulation of heart rate | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Heart-rate physiology is a downstream tissue-level consequence of calmodulin ion-channel regulation, not the primary molecular function of Calm2. Reason: Tissue-specific or specialized function |
| GO:0005246 calcium channel regulator activity | ISO GO_REF:0000119 | ACCEPT | Summary: Regulates L-type calcium channels and ryanodine receptors Reason: Core calmodulin function or localization |
| GO:0005509 calcium ion binding | ISO GO_REF:0000096 | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization |
| GO:0005509 calcium ion binding | ISO GO_REF:0000119 | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | ISO GO_REF:0000119 | ACCEPT | Summary: Core calcium sensing function Reason: Core calmodulin function or localization |
| GO:0005634 nucleus | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Nuclear localization is plausible for calmodulin but rat paralog transfers do not justify treating it as a Calm2-specific core localization. Reason: Paralog-sensitive ISO transfer reflects specialized context rather than a Calm2 core role |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization |
| GO:0005813 centrosome | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Centrosomal localization for cell division Reason: Tissue-specific or specialized function |
| GO:0005876 spindle microtubule | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Spindle microtubule association Reason: Tissue-specific or specialized function |
| GO:0008179 adenylate cyclase binding | ISO GO_REF:0000119 | ACCEPT | Summary: Calmodulin directly binds calmodulin-responsive adenylate cyclases, a broadly conserved signaling interaction consistent with the identical CALM proteins. Reason: Core calmodulin function or localization |
| GO:0010856 adenylate cyclase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: Activates adenylate cyclase for cAMP signaling Reason: Core calmodulin function or localization |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | ISO GO_REF:0000119 | ACCEPT | Summary: Regulates RyR-mediated calcium release from SR Reason: Core calmodulin function or localization |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cardiac calcium-induced calcium release is a tissue-specific physiological context downstream of calmodulin channel regulation. Reason: Tissue-specific or specialized function |
| GO:0019855 calcium channel inhibitor activity | ISO GO_REF:0000119 | ACCEPT | Summary: Inhibits IP3 receptors and certain calcium channels Reason: Core calmodulin function or localization |
| GO:0019901 protein kinase binding | ISO GO_REF:0000119 | ACCEPT | Summary: Binds CaMK family and other protein kinases Reason: Core calmodulin function or localization |
| GO:0019904 protein domain specific binding | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: This parent binding term is too generic, and the rat-source ISO transfer does not add a Calm2-specific mechanistic claim. Reason: Too general and supported only by paralog-sensitive ISO transfer |
| GO:0030017 sarcomere | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Sarcomere localization in muscle Reason: Tissue-specific or specialized function |
| GO:0030235 nitric-oxide synthase regulator activity | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Regulation of nitric-oxide synthases is plausible for calmodulin proteins, but this rat paralog transfer is not strong enough to make it a core Calm2-specific function. Reason: Specialized interaction inferred from paralog-sensitive ISO transfer |
| GO:0030426 growth cone | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Growth-cone localization comes from rat calmodulin paralogs that all carry the same annotation, so this is likely family-wide contextual localization rather than a specific Calm2 assignment. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0030672 synaptic vesicle membrane | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Synaptic vesicle membrane localization is based on rat Calm1/2/3 transfers and is better treated as specialized contextual localization for the individual Calm2 locus. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0031432 titin binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Titin binding in muscle Reason: Tissue-specific or specialized function |
| GO:0031800 type 3 metabotropic glutamate receptor binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Specific metabotropic glutamate receptor binding is not established directly for mouse Calm2 and the supporting ISO source is a rat paralog family transfer. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction |
| GO:0031966 mitochondrial membrane | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Mitochondrial membrane localization appears in all three rat calmodulin paralogs and is better treated as contextual, non-core localization for mouse Calm2. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0032465 regulation of cytokinesis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cytokinesis regulation with CP110 and centrin Reason: Tissue-specific or specialized function |
| GO:0032991 protein-containing complex | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Too general - more specific terms available Reason: Too general - more specific terms are available |
| GO:0034704 calcium channel complex | ISO GO_REF:0000119 | ACCEPT | Summary: Component of calcium channel complexes Reason: Core calmodulin function or localization |
| GO:0043209 myelin sheath | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Myelin-associated calmodulin interactions are plausible, but the rat paralog ISO transfer is too nonspecific to treat this as a direct Calm2 locus assignment. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0043539 protein serine/threonine kinase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: Activates CaMKII and other calcium-dependent kinases Reason: Core calmodulin function or localization |
| GO:0043548 phosphatidylinositol 3-kinase binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: PI3K binding is a specific interaction claim not resolved cleanly for mouse Calm2 by rat paralog transfer. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000096 | ACCEPT | Summary: The rat-source version of this broad transporter-binding annotation is redundant with stronger human-source transfer and is not independently informative, but the term itself is consistent with family-wide calmodulin channel/transporter binding. Reason: Core calmodulin function or localization |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000119 | ACCEPT | Summary: Binds ion channels and transporters Reason: Core calmodulin function or localization |
| GO:0048306 calcium-dependent protein binding | ISO GO_REF:0000096 | ACCEPT | Summary: Calcium-dependent target protein binding Reason: Core calmodulin function or localization |
| GO:0050998 nitric-oxide synthase binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Nitric-oxide synthase binding is plausible for calmodulin proteins, but here it is supported only through rat paralog transfer and is best kept as specialized, non-core biology. Reason: Specialized interaction inferred from paralog-sensitive ISO transfer |
| GO:0051592 response to calcium ion | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Response to calcium ion Reason: Tissue-specific or specialized function |
| GO:0055117 regulation of cardiac muscle contraction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cardiac contraction is a downstream tissue-level process; the direct supported function is calcium/channel regulation. Reason: Tissue-specific or specialized function |
| GO:0072542 protein phosphatase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: Activates calcineurin (PP2B) phosphatase Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | ISO GO_REF:0000119 | ACCEPT | Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization |
| GO:0098685 Schaffer collateral - CA1 synapse | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: This hippocampal synapse annotation is shared across rat calmodulin paralogs and is too context-specific to transfer cleanly onto the mouse Calm2 locus. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0099523 presynaptic cytosol | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Presynaptic cytosol localization from rat paralog transfer is too source-ambiguous for a standalone ISO claim on mouse Calm2. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0099524 postsynaptic cytosol | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Postsynaptic cytosol localization from rat paralog transfer is too source-ambiguous for a standalone ISO claim on mouse Calm2. Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cardiac conduction effects are consistent with calmodulin regulation of ion channels, but this remains a specialized physiological context rather than a universal Calm2 role. Reason: Specialized physiological context rather than core Calm2 biochemistry |
| GO:1902494 catalytic complex | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Catalytic complex is too generic to be useful and adds no mechanistic precision beyond more specific binding and channel-complex terms. Reason: Too general - more specific terms are available |
| GO:0141110 transporter inhibitor activity | IDA PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | KEEP AS NON CORE | Summary: Calmodulin suppresses stimulated NCKX4 activity, supporting transporter inhibitor activity in a specific exchanger context. Reason: Direct mouse evidence supports a specialized transporter-regulatory role Supporting Evidence: PMID:33199372 coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient calmodulin mutant, suppressed NCKX4 activation in a time-dependent manner |
| GO:0044305 calyx of Held | IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: The study was performed at the calyx of Held and shows a specialized neuronal context for Calm2-dependent endocytosis. Reason: Direct mouse evidence supports a specialized neuronal localization Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces |
| GO:0044305 calyx of Held | IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: Localization to the calyx of Held is experimentally supported but represents a specialized neuronal compartment. Reason: Direct mouse evidence supports a specialized neuronal localization Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces |
| GO:0099523 presynaptic cytosol | IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: Calm2 knockout mice show presynaptic defects at calyx and hippocampal synapses, supporting a real but specialized presynaptic role. Reason: Direct mouse evidence supports a specialized neuronal function Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces |
| GO:0099523 presynaptic cytosol | IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: Experiments at calyx and hippocampal synapses support presynaptic cytosol localization, but this remains specialized neuronal biology rather than a core Calm2 localization. Reason: Direct mouse evidence supports a specialized neuronal localization Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces |
| GO:0140238 presynaptic endocytosis | IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: Calm2 knockout impairs calcium-stimulated synaptic endocytosis, supporting a genuine but specialized role in presynaptic endocytosis. Reason: Direct mouse evidence supports a specialized neuronal function Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces, and inhibited slow endocytosis and bulk endocytosis (forming large endosome-like structures) at small conventional hippocampal synapses |
| GO:0140238 presynaptic endocytosis | IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: The synaptic physiology study supports presynaptic endocytic involvement, but this is a specialized synaptic role rather than a core calmodulin function. Reason: Direct mouse evidence supports a specialized neuronal function Supporting Evidence: PMID:31628181 We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces, and inhibited slow endocytosis and bulk endocytosis (forming large endosome-like structures) at small conventional hippocampal synapses |
| GO:0005515 protein binding | IPI PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | MARK AS OVER ANNOTATED | Summary: The NCKX4 study shows a specific calcium-dependent interaction, but protein binding is too generic to retain as an informative molecular function. Reason: Too general - more specific terms are available Supporting Evidence: PMID:33199372 Calmodulin binding to NCKX4 was demonstrated in extracts from mouse brain and in transfected HEK293 cells |
| GO:0016020 membrane | IDA PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | MARK AS OVER ANNOTATED | Summary: This study examined calmodulin bound to a membrane transporter; it does not establish Calm2 as a stable membrane component. Reason: Over-annotated localization derived from interaction context rather than stable residence Supporting Evidence: PMID:33199372 calmodulin bound to NCKX4 under basal conditions and induced a ∼2.5-fold increase in NCKX4 abundance, but did not influence either cellular location or basal activity |
| GO:0031982 vesicle | IDA PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | MARK AS OVER ANNOTATED | Summary: Association with transporter-containing fractions does not justify a general vesicle localization for Calm2. Reason: Over-annotated localization derived from interaction context rather than stable residence Supporting Evidence: PMID:33199372 Calmodulin binding to NCKX4 was demonstrated in extracts from mouse brain and in transfected HEK293 cells |
| GO:0048306 calcium-dependent protein binding | IPI PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | ACCEPT | Summary: Direct interaction with NCKX4 supports the core calmodulin property of calcium-dependent binding to target proteins. Reason: Core calmodulin function or localization Supporting Evidence: PMID:33199372 Calmodulin bound in a Ca2+-dependent manner to a motif present in the central cytosolic loop of NCKX4 and was abolished by the double-mutant I328D/F334D |
| GO:0050848 regulation of calcium-mediated signaling | IGI PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | ACCEPT | Summary: Calmodulin is a central calcium sensor, and NCKX4 genetic interaction data support a real role in regulating calcium-mediated signaling. Reason: Core calmodulin function or localization Supporting Evidence: PMID:33199372 We propose that Ca2+ binding to calmodulin prepositioned on NCKX4 induces a slow conformational rearrangement that interferes with purinergic stimulation of the exchanger, possibly by obscuring T331, a previously identified potential protein kinase C site |
| GO:1905913 negative regulation of calcium ion export across plasma membrane | IDA PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-e... | KEEP AS NON CORE | Summary: The NCKX4 study supports inhibition of calcium export across the plasma membrane in a specific transporter context, not a universal Calm2 role. Reason: Direct mouse evidence supports a specialized transporter-regulatory role Supporting Evidence: PMID:33199372 coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient calmodulin mutant, suppressed NCKX4 activation in a time-dependent manner |
| GO:0043209 myelin sheath | IDA PMID:19855925 Structural analysis of the complex between calmodulin and fu... | KEEP AS NON CORE | Summary: Myelin sheath localization Reason: Tissue-specific or specialized function Supporting Evidence: PMID:19855925 CaM and MBP colocalize in myelin sheaths. |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization |
| GO:0019855 calcium channel inhibitor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Inhibits IP3 receptors and certain calcium channels Reason: Core calmodulin function or localization |
| GO:0060315 negative regulation of ryanodine-sensitive calcium-release channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Inhibits ryanodine receptor under certain conditions Reason: Core calmodulin function or localization |
| GO:0008076 voltage-gated potassium channel complex | IGI PMID:12223552 Calmodulin is an auxiliary subunit of KCNQ2/3 potassium chan... | KEEP AS NON CORE | Summary: KCNQ channel complex component Reason: Tissue-specific or specialized function Supporting Evidence: PMID:12223552 Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels. |
| GO:0000086 G2/M transition of mitotic cell cycle | IDA PMID:2469574 Calmodulin is required for cell-cycle progression during G1 ... | KEEP AS NON CORE | Summary: Cell cycle regulation at G2/M transition Reason: Tissue-specific or specialized function Supporting Evidence: PMID:2469574 Calmodulin is required for cell-cycle progression during G1 and mitosis. |
| GO:0005509 calcium ion binding | TAS PMID:2469574 Calmodulin is required for cell-cycle progression during G1 ... | ACCEPT | Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization Supporting Evidence: PMID:2469574 Calmodulin is required for cell-cycle progression during G1 and mitosis. |
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Download this section (compressed HTML)Q: Which mouse calmodulin locus supplies the calmodulin protein detected at specialized neuronal compartments where rat Calm1/2/3 currently share the same annotations?
Q: Can orthology-transfer rules for ISO annotations be tightened for identical-protein paralog families such as Calm1/Calm2/Calm3 to avoid locus-specific over-transfer?
Experiment: Use endogenous locus-specific tagging or targeted proteomics to measure Calm1, Calm2, and Calm3 contributions in presynaptic terminals, myelin, and cardiomyocytes.
Hypothesis: Specialized neuronal and glial localizations currently transferred by ISO reflect locus-specific expression differences more than unique protein chemistry.
Type: Endogenous tagging and quantitative proteomics
Experiment: Perform promoter-aware rescue experiments in Calm2 knockout neurons and cardiomyocytes with each calmodulin paralog to separate protein-level interchangeability from locus-specific regulation.
Hypothesis: The encoded proteins will be largely interchangeable biochemically, but rescue strength will depend on the regulatory context of each locus.
Type: Genetic rescue under native or promoter-swapped expression
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