Calmodulin-3 is one of three mouse calmodulin genes (Calm1, Calm2, Calm3) that all encode the same 149 aa calcium sensor protein. Calm3 is the most brain-enriched of the three paralogs, with high expression in hippocampus, cerebellum, and neurons generally, though the protein is broadly expressed. The protein is also identical to human and rat calmodulin. Its core activities are calcium binding through four EF-hands and calcium-dependent regulation of targets such as CaMKII, calcineurin and ion channels; it also acts at the mitotic spindle and centrosome and in synaptic, cardiac and sarcomeric contexts. Calm3 has a unique post-transcriptional regulatory feature — the long Calm3 isoform (Calm3L) contains a retained intron in its 3-UTR that recruits Staufen2 (Stau2) and drives activity-dependent localization of Calm3 mRNA specifically to neuronal dendrites (PMID:28765142). This mechanism is absent for Calm1 and Calm2. Stau2 iCLIP in E18 mouse brain showed Calm3 as the top retained-intron Stau2 target (0.24% of all tags), while Calm1/Calm2 lack crosslink clusters. NMDA stimulation promotes and synaptic silencing reduces this dendritic targeting. This supports a Calm3-specific mRNA-localization mechanism, but does not by itself demonstrate Calm3 protein localization to the postsynaptic cytosol, so postsynaptic-cytosol annotations are treated as specialized non-core context. The calyx-of-Held and presynaptic-endocytosis annotations (PMID:31628181) derive from Calm2-knockout experiments, not Calm3, and are treated accordingly. Calm3-specific interaction evidence also exists for RYR1, RYR2, SYT7, and IQCF1 (PubMed:18650434, 24569478, 25380116).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Primary cytoplasmic localization shared by all calmodulin proteins 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; identical protein to CALM1/2/3 Reason: Core calmodulin function or localization |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization is established for calmodulin but is context-specific; not a universal Calm3-defining localization 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; supported by direct evidence for RYR1/RYR2 interaction (PMID:18650434) Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | IBA GO_REF:0000033 | ACCEPT | Summary: Core calcium sensing function; canonical calmodulin activity Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: Activates calcineurin phosphatase for NFAT-pathway signaling; broadly conserved calmodulin function 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: CaM localizes to myelin via MBP interaction (PMID:19855925) but represents neural-specific context 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; supported by direct IDA evidence for calmodulin but not a core Calm3 molecular function 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; redundant with IBA but consistent 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; synaptic context more specific — parent term too general here Reason: Tissue-specific or specialized function |
| GO:0051649 establishment of localization in cell | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Too general; adds no mechanistic specificity for Calm3 Reason: Too general — more specific terms are available |
| GO:0098793 presynapse | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Presynaptic enrichment is plausible given Calm3 brain expression but represents specialized neuronal context rather than a universal Calm3 localization Reason: Tissue-specific or specialized function |
| GO:0150034 distal axon | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Distal axon localization is neuronal-context specific Reason: Tissue-specific or specialized function |
| GO:0000785 chromatin | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Chromatin association is not a primary Calm3 localization; carried over from family-wide annotation Reason: Tissue-specific or specialized function |
| GO:0001975 response to amphetamine | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Amphetamine response in dopaminergic neurons; very context-specific Reason: Tissue-specific or specialized function |
| GO:0002027 regulation of heart rate | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Heart rate regulation through ion channel modulation is a cardiac physiological context of calmodulin channel regulation, not a universal Calm3 core function Reason: Tissue-specific or specialized function |
| GO:0005246 calcium channel regulator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Regulates L-type calcium channels, RyR, and other calcium channels; core calmodulin activity Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | IEA GO_REF:0000120 | ACCEPT | Summary: Core calcium sensing function; redundant with IBA Reason: Core calmodulin function or localization |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear localization is context-specific for calmodulin; not a Calm3-defining annotation Reason: Tissue-specific or specialized function |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Primary cytoplasmic localization; core 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 calcium sensor; core Reason: Core calmodulin function or localization |
| GO:0005876 spindle microtubule | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Spindle microtubule association during mitosis Reason: Tissue-specific or specialized function |
| GO:0008179 adenylate cyclase binding | IEA GO_REF:0000120 | ACCEPT | Summary: Calmodulin directly binds calmodulin-sensitive adenylate cyclases (AC1, AC8); broadly conserved Reason: Core calmodulin function or localization |
| GO:0010856 adenylate cyclase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates calcium-dependent adenylate cyclases 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; supported by RYR1/RYR2 interaction evidence 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 regulation is consistent with calmodulin regulation of RyR channels but is cardiac-specific downstream physiology Reason: Tissue-specific or specialized function |
| GO:0016240 autophagosome membrane docking | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Autophagosome docking; no specific evidence for Calm3 at this process; specialized context Reason: Tissue-specific or specialized function |
| GO:0019855 calcium channel inhibitor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Inhibitory regulation of certain calcium channels (IP3 receptor inhibition, RyR inhibition at high calcium); broadly conserved calmodulin function Reason: Core calmodulin function or localization |
| GO:0019901 protein kinase binding | IEA GO_REF:0000120 | ACCEPT | Summary: Binds CaMKII, CaMKIV, and other calmodulin-dependent kinases; core calmodulin activity Reason: Core calmodulin function or localization |
| GO:0019904 protein domain specific binding | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Parent binding term too generic; does not capture specific calmodulin-recognition motif interactions Reason: Too general — more specific terms are available |
| GO:0030017 sarcomere | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Sarcomere localization in striated muscle; calmodulin binds titin and myosin light chains; tissue-specific context Reason: Tissue-specific or specialized function |
| GO:0030235 nitric-oxide synthase regulator activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Calmodulin activates eNOS, nNOS, and iNOS; plausible but represents specialized context Reason: Tissue-specific or specialized function |
| GO:0030426 growth cone | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Growth cone localization for axon guidance signaling; neuronal-specific context Reason: Tissue-specific or specialized function |
| GO:0030672 synaptic vesicle membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Synaptic vesicle membrane association; neuronal-specific; SYT7 interaction supports synaptic context (PMID:24569478) but doesn't establish vesicle membrane localization for Calm3 specifically Reason: Tissue-specific or specialized function |
| GO:0031432 titin binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Titin binding in muscle; tissue-specific context 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; specific neuronal interaction not directly established for mouse Calm3 Reason: Tissue-specific or specialized function |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Mitochondrial membrane association; likely contextual localization carried from family-wide annotation Reason: Tissue-specific or specialized function |
| GO:0032465 regulation of cytokinesis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytokinesis regulation with CCP110 and centrin Reason: Tissue-specific or specialized function |
| GO:0032991 protein-containing complex | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Too generic; adds no specificity beyond targeted complex terms already present Reason: Too general — more specific terms are available |
| GO:0034704 calcium channel complex | IEA GO_REF:0000120 | ACCEPT | Summary: Component of calcium channel complexes (RyR1, RyR2, L-type Ca2+ channels); core calmodulin function supported by direct interaction evidence 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; likely indirect/pathway association; specialized context Reason: Tissue-specific or specialized function |
| GO:0043209 myelin sheath | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Myelin sheath localization; supported by direct IDA evidence (PMID:19855925) for CaM-MBP complex in myelin; but Calm3 identity in the study is not established — general calmodulin protein Reason: Tissue-specific or specialized function |
| GO:0043539 protein serine/threonine kinase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates CaMKII, CaMKIV, MLCK, and other calcium-dependent kinases; core calmodulin function Reason: Core calmodulin function or localization |
| GO:0043548 phosphatidylinositol 3-kinase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PI3K binding; specific signaling interaction not independently established for mouse Calm3 Reason: Tissue-specific or specialized function |
| GO:0044325 transmembrane transporter binding | IEA GO_REF:0000120 | ACCEPT | Summary: Binds ion channels and transporters; consistent with calmodulin's role in channel regulation 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; indirect/computed association; specialized context Reason: Tissue-specific or specialized function |
| GO:0048306 calcium-dependent protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Calcium-dependent target protein binding; core calmodulin activity Reason: Core calmodulin function or localization |
| GO:0050998 nitric-oxide synthase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Binding to NOS isoforms; biologically plausible but specialized context Reason: Tissue-specific or specialized function |
| GO:0051412 response to corticosterone | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Corticosterone response in neurons; very specialized, indirect 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; too generic — more specific calcium-sensing and detection terms capture the relevant biology Reason: Too general — more specific terms capture this function better |
| GO:0055117 regulation of cardiac muscle contraction | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cardiac contraction regulation reflects tissue-specific physiology downstream of core calmodulin 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; indirect/computed association; specialized context Reason: Tissue-specific or specialized function |
| GO:0072542 protein phosphatase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Activates calcineurin (PP2B) phosphatase; core calmodulin function in Ca2+-calcineurin-NFAT signaling Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | IEA GO_REF:0000120 | ACCEPT | Summary: Calcineurin activation for NFAT signaling; core, redundant with IBA entry Reason: Core calmodulin function or localization |
| GO:0098685 Schaffer collateral - CA1 synapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Hippocampal CA1 synapse localization; neuronal-specific context; consistent with Calm3 brain enrichment but represents specialized rather than universal Calm3 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 through L-type Ca channel and KCNQ modulation; well-established for calmodulin but cardiac-specific context Reason: Tissue-specific or specialized function |
| GO:0099523 presynaptic cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Presynaptic cytosol localization; neuronal-specific; relevant for Calm3's synaptic role but treats specialized context as universal Reason: Tissue-specific or specialized function |
| GO:0099524 postsynaptic cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Postsynaptic cytosol localization; supported by Calm3-specific dendritic mRNA targeting via Stau2 (PMID:28765142), but that evidence is for mRNA localization and does not directly establish Calm3 protein localization to postsynaptic cytosol Reason: Neuronal compartment-specific context supported indirectly by Calm3 mRNA localization |
| GO:0140056 organelle localization by membrane tethering | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Organelle membrane tethering; indirect/computed association 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; neuronal-specific; see also IDA/IMP entries from PMID:31628181 (Calm2 KO study) 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; specialized cardiac context Reason: Tissue-specific or specialized function |
| GO:1902494 catalytic complex | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Too generic; adds no specificity beyond more precise complex and binding 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; indirect/computed association; specialized context 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; neuronal-specific; SYT7 interaction (PMID:24569478) supports synaptic role but does not establish Calm3-specific exocytosis control Reason: Tissue-specific or specialized function |
| GO:1901842 negative regulation of high voltage-gated calcium channel activity | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog) (identical protein); inhibitory regulation of L-type Ca channels is well-established for calmodulin and consistent with RyR regulatory roles; transfer is valid Reason: Core calmodulin function or localization |
| GO:0000785 chromatin | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: WITH/FROM names only rat Calm1 (RGD:2257), a paralog of mouse Calm3. Rat Calm3 (P0DP31) currently carries the same IDA (PMID:17482793), so an ortholog donor also exists. Chromatin association is contextual, not a Calm3-defining localization Reason: Paralog-sourced ISO transfer of an identical protein; reflects specialized context rather than a Calm3 core role Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: RGD:2257 · rat Calm1 SUPPORTS TRANSFER Paralog donor; protein identical to mouse Calm3, so the localization transfers UniProtKB:P0DP31 · rat Calm3 SUPPORTS TRANSFER Ortholog carries the same IDA (PMID:17482793) but is not named in WITH/FROM |
| GO:0000922 spindle pole | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); 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: ISO transfer from human CALM3 (ortholog); heart rate regulation through ion channel modulation is cardiac physiological context downstream of core calmodulin channel regulation Reason: Tissue-specific or specialized function |
| GO:0005246 calcium channel regulator activity | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); calcium channel regulation is core calmodulin function; transfer is valid and supported by direct RYR1/RYR2 interaction evidence for this protein Reason: Core calmodulin function or localization |
| GO:0005509 calcium ion binding | ISO GO_REF:0000096 | ACCEPT | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); core EF-hand calcium-binding function; valid regardless of rat paralog source Reason: Core calmodulin function or localization |
| GO:0005509 calcium ion binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); core EF-hand calcium-binding function; redundant but valid Reason: Core calmodulin function or localization |
| GO:0005513 detection of calcium ion | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); core calcium sensing function; transfer is valid Reason: Core calmodulin function or localization |
| GO:0005634 nucleus | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); nuclear localization is plausible but context-specific; paralog-sensitive transfer does not justify treating as Calm3 core localization Reason: Paralog-sensitive ISO transfer reflects specialized context rather than a Calm3 core role |
| GO:0005813 centrosome | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); centrosomal localization for cell division Reason: Tissue-specific or specialized function |
| GO:0005876 spindle microtubule | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); spindle microtubule association during mitosis Reason: Tissue-specific or specialized function |
| GO:0008179 adenylate cyclase binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); calmodulin binds calmodulin-sensitive adenylate cyclases; broadly conserved interaction; valid transfer Reason: Core calmodulin function or localization |
| GO:0010856 adenylate cyclase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); activates calcium-dependent adenylate cyclases; valid transfer 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: ISO transfer from human CALM3 (ortholog); SR calcium release via RyR regulation; valid transfer supported by direct RYR1/RYR2 interaction evidence (PMID:18650434) 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: ISO transfer from human CALM3 (ortholog); cardiac calcium-induced calcium release is valid but cardiac-specific downstream physiology rather than a universal Calm3 core function Reason: Tissue-specific or specialized function |
| GO:0019901 protein kinase binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); calmodulin binds CaMK family and other kinases; broadly conserved; valid transfer Reason: Core calmodulin function or localization |
| GO:0019904 protein domain specific binding | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Too generic; the ISO transfer, from rat Calm1 (RGD:2257) alone, a paralog of mouse Calm3, adds no mechanistic specificity for Calm3; same issue as the IEA version of this term Reason: Too general and supported only by paralog-sensitive ISO transfer |
| GO:0030017 sarcomere | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); sarcomere localization in striated muscle; tissue-specific context Reason: Tissue-specific or specialized function |
| GO:0030235 nitric-oxide synthase regulator activity | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); NOS regulation is plausible but not a Calm3-defining function; paralog-sensitive transfer Reason: Paralog-sensitive ISO transfer supports only specialized, non-core function |
| GO:0030426 growth cone | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); growth cone localization is neuronal-specific; paralog-sensitive transfer lacking Calm3-specific evidence 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: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); synaptic vesicle membrane localization is neuronal-specific; paralog-sensitive transfer; consistent with SYT7 interaction (PMID:24569478) but does not establish Calm3 specifically at this compartment Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0031432 titin binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); titin binding in muscle sarcomere; tissue-specific context Reason: Tissue-specific or specialized function |
| GO:0031800 type 3 metabotropic glutamate receptor binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1 (RGD:2257) alone, a paralog of mouse Calm3; mGluR3 binding is a specific neuronal interaction not directly established for mouse Calm3; paralog-sensitive 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: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); mitochondrial membrane localization is contextual; paralog-sensitive transfer lacks Calm3-specific support 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: ISO transfer from human CALM3 (ortholog); cytokinesis regulation with CCP110 and centrin Reason: Tissue-specific or specialized function |
| GO:0032991 protein-containing complex | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Too generic; adds no specificity beyond more precise complex terms; same concern as IEA version Reason: Too general — more specific terms are available |
| GO:0034704 calcium channel complex | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); calmodulin is a component of calcium channel complexes; supported by direct RYR1/RYR2 interaction evidence; valid transfer Reason: Core calmodulin function or localization |
| GO:0043209 myelin sheath | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); myelin sheath localization supported by IDA (PMID:19855925) for CaM-MBP complex; but the study used general CaM, not Calm3-specific; paralog-sensitive transfer consistent with specialized context 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: ISO transfer from human CALM3 (ortholog); activates CaMKII, CaMKIV, MLCK; core calmodulin function; valid transfer Reason: Core calmodulin function or localization |
| GO:0043548 phosphatidylinositol 3-kinase binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1 (RGD:2257) alone, a paralog of mouse Calm3; PI3K binding is a specific interaction not independently established for mouse Calm3; paralog-sensitive transfer Reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000096 | ACCEPT | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); broad transporter-binding; valid at protein level; consistent with channel-regulation function Reason: Core calmodulin function or localization |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); binds ion channels and transporters; valid transfer; core calmodulin channel-regulation function Reason: Core calmodulin function or localization |
| GO:0048306 calcium-dependent protein binding | ISO GO_REF:0000096 | ACCEPT | Summary: ISO transfer from rat Calm1 (RGD:2257) alone, a paralog of mouse Calm3; calcium-dependent target protein binding is core calmodulin function; valid transfer Reason: Core calmodulin function or localization |
| GO:0050998 nitric-oxide synthase binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); NOS binding is plausible but represents specialized context; paralog-sensitive transfer lacks Calm3-specific support Reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction |
| GO:0051592 response to calcium ion | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); too generic — the detection and sensing terms capture the core biology more precisely Reason: Too general — more specific terms capture this function better |
| GO:0055117 regulation of cardiac muscle contraction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); cardiac contraction regulation is a tissue-specific physiological consequence of calmodulin ion-channel regulation Reason: Tissue-specific or specialized function |
| GO:0072542 protein phosphatase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); activates calcineurin (PP2B) phosphatase; core calmodulin function; valid transfer Reason: Core calmodulin function or localization |
| GO:0097720 calcineurin-mediated signaling | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human CALM3 (ortholog); calcineurin activation; redundant with IBA but valid transfer Reason: Core calmodulin function or localization |
| GO:0098685 Schaffer collateral - CA1 synapse | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); hippocampal CA1 synapse localization; very specific neuronal context; Calm3 is brain-enriched but this level of specificity cannot be assigned solely from paralog ISO transfer Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0098901 regulation of cardiac muscle cell action potential | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human CALM3 (ortholog); cardiac action potential regulation; valid transfer but specialized cardiac context rather than a universal Calm3 function Reason: Tissue-specific or specialized function |
| GO:0099523 presynaptic cytosol | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); presynaptic cytosol localization; neuronal-specific; Calm3 brain enrichment makes this plausible but the paralog transfer from all three rat Calm genes lacks Calm3-specific evidence Reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization |
| GO:0099524 postsynaptic cytosol | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO transfer from rat Calm1, Calm2 and Calm3 (RGD:2257, 2258, 2259; only Calm3 is the ortholog); Calm3L mRNA is uniquely targeted to neuronal dendrites via Stau2 (PMID:28765142), but mRNA localization does not directly demonstrate Calm3 protein localization to postsynaptic cytosol 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: ISO transfer from human CALM3 (ortholog); cardiac gap junction/conduction regulation; valid transfer but specialized cardiac context Reason: Tissue-specific or specialized function |
| GO:1902494 catalytic complex | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: ISO transfer from human CALM3 (ortholog); too generic; adds no specificity beyond more precise complex and binding terms Reason: Too general — more specific terms are available |
| GO:0044305 calyx of Held | NAS PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: PMID:31628181 used Calm2 knockout mice (not Calm3) to study calcium-stimulated endocytosis at calyx of Held synapses; NAS (non-traceable author statement) attribution to Calm3 (P0DP28) is based on protein identity; annotation reflects family-level calmodulin biology at this synapse rather than Calm3-specific evidence Reason: Experimental basis is Calm2 KO; attributed to Calm3 via protein identity rather than direct Calm3 experimental evidence |
| GO:0044305 calyx of Held | IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: PMID:31628181 used Calm2 knockout mice; the IMP annotation is attributed to Calm3 (P0DP28) based on protein identity but the mutant was Calm2-specific; the phenotype was observed in Calm2 KO, not Calm3 KO; kept as non-core consistent with other calyx entries Reason: Experimental basis is Calm2 KO; attributed to Calm3 via protein identity rather than direct Calm3 experimental evidence |
| GO:0044305 calyx of Held | IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: IDA from SynGO curation of PMID:31628181; SynGO annotated calmodulin protein presence at calyx of Held; calmodulin protein (identical across all three mouse paralogs) is detected at this synapse; localization evidence is valid at protein level but Calm3-specificity is not established Reason: Valid protein-level localization evidence but not Calm3-specific; Calm2 is the paralog with direct knockout evidence at this synapse |
| GO:0140238 presynaptic endocytosis | NAS PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: NAS from PMID:31628181; presynaptic endocytosis at calyx of Held; same provenance issue as calyx-of-Held NAS — experiment used Calm2 KO; annotation to Calm3 by protein identity Reason: Experimental basis is Calm2 KO; attributed to Calm3 via protein identity rather than direct Calm3 experimental evidence |
| GO:0140238 presynaptic endocytosis | IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: IMP from PMID:31628181; mutant phenotype from Calm2 KO used to infer Calm3 function; same provenance concern as calyx-of-Held — experiment used Calm2 KO not Calm3 KO; kept as non-core consistent with other presynaptic endocytosis entries Reason: Experimental basis is Calm2 KO; attributed to Calm3 via protein identity rather than direct Calm3 experimental evidence |
| GO:0140238 presynaptic endocytosis | IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for... | KEEP AS NON CORE | Summary: IDA from SynGO curation; calmodulin's role in presynaptic endocytosis is established but not Calm3-specific; consistent with Calm3 brain expression context Reason: Valid protein-level functional evidence but not Calm3-specific |
| GO:0098901 regulation of cardiac muscle cell action potential | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS manual transfer; cardiac action potential regulation is well-established for calmodulin; specialized cardiac context rather than a universal Calm3 role Reason: Tissue-specific or specialized function |
| GO:1901842 negative regulation of high voltage-gated calcium channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS manual transfer; inhibitory regulation of L-type Ca channels by calmodulin; well-established calmodulin function; consistent with ISO entry for same term Reason: Core calmodulin function or localization |
| GO:0043209 myelin sheath | IDA PMID:19855925 Structural analysis of the complex between calmodulin and fu... | KEEP AS NON CORE | Summary: PMID:19855925 demonstrates CaM-MBP complex in myelin sheaths via SAXS/NMR and colocalization; the study uses general calmodulin protein (not Calm3-specific) isolated from human brain; localization evidence is attributed to P0DP28 (Calm3) via CAFA database assignment; Calm3 is expressed in brain where myelin is present so the annotation is plausible but represents specialized context Reason: IDA evidence is for calmodulin protein in general, not specifically Calm3; specialized neural context |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS manual transfer; core EF-hand calcium binding; redundant with IBA but confirms this core function 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: PMID:12223552 (Wen & Levitan 2002) identifies calmodulin as a constitutive auxiliary subunit of KCNQ2/3 potassium channels in mouse brain using yeast two-hybrid and co-immunoprecipitation; uses general calmodulin (from mouse brain) not specifically Calm3; IGI evidence is for the calmodulin protein interacting with KCNQ genes; valid but Calm3-specificity is not established Reason: Evidence is for calmodulin protein generally, not Calm3 specifically; specialized neuronal context |
| 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: PMID:2469574 (Rasmussen & Means 1989) uses inducible antisense RNA to reduce calmodulin in mouse C127 cells, causing cell cycle arrest at G1 and mitosis; the antisense targets total calmodulin (CaM), not specifically Calm3; direct evidence for calmodulin cell cycle requirement; core function consistent with centrosome/spindle annotations Reason: Tissue-specific or specialized function; IDA evidence supports calmodulin requirement in cell cycle progression but not core Calm3 molecular function |
| GO:0005509 calcium ion binding | TAS PMID:2469574 Calmodulin is required for cell-cycle progression during G1 ... | ACCEPT | Summary: TAS (traceable author statement) for calcium ion binding from PMID:2469574; core EF-hand function; redundant with IBA/ISS entries Reason: Core calmodulin function or localization Supporting Evidence: file:mouse/Calm3/Calm3-deep-research-falcon.md |
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Download this section (compressed HTML)Q: Is Calm3 preferentially recruited over Calm1 or Calm2 at brain synapses, or are all three calmodulin paralogs functionally interchangeable at this location?
Q: What is the basis for the calyx-of-Held and presynaptic endocytosis IDA annotations being attributed to Calm3 (P0DP28) by SynGO when the knockout experiment in PMID:31628181 specifically used Calm2?
Q: Do Calm1, Calm2, and Calm3 have distinct expression profiles across mouse brain cell types that would justify differential annotation of synaptic, cardiac, or other specialized terms to specific paralogs?
Experiment: Calm3-specific knockout at calyx of Held synapses to test whether Calm3 makes a distinct contribution to presynaptic endocytosis independent of Calm2
Hypothesis: Calm3, as the most brain-enriched calmodulin paralog, may be specifically required at certain synapses even though all three calmodulin proteins are biochemically identical
Type: Conditional gene knockout and synaptic physiology
Experiment: Single-cell RNA-seq comparison of Calm1, Calm2, and Calm3 expression across mouse brain cell types to determine if any calmodulin paralog is preferentially expressed in specific neuronal populations
Hypothesis: Calm3 may show distinct cell-type enrichment that would justify differential assignment of neuronal ISO annotations to Calm3 versus Calm1/Calm2
Type: Single-cell transcriptomics
Experiment: Generate calmodulin paralog-specific antibodies or endogenous epitope tags to determine whether Calm3 protein specifically localizes to synaptic vesicle membrane, presynaptic cytosol, or myelin sheath at the protein level
Hypothesis: Calm3-encoded protein may be preferentially present at certain subcellular compartments due to local translation or differential mRNA localization
Type: Endogenous tagging and subcellular proteomics
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