Existing Annotations Review

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.

Core Functions

Primary intracellular calcium sensor that binds calcium through four EF-hand motifs and converts calcium binding into target regulation.

Molecular Function:

calcium ion binding

Directly Involved In:

detection of calcium ion

Cellular Locations:

cytosol

Supporting Evidence:

UniProtKB:P0DP27
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.
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.

Regulates calcium channels and exchangers, including ryanodine receptors and NCKX4, to tune calcium release and calcium export.

Molecular Function:

calcium channel regulator activity

Directly Involved In:

regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum negative regulation of ryanodine-sensitive calcium-release channel activity

In Complex:

calcium channel complex

Supporting Evidence:

PMID:33199372
When purinergic stimulation of NCKX4 was examined in these cells, coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient calmodulin mutant, suppressed NCKX4 activation in a time-dependent manner
UniProtKB:P0DP27
Mediates calcium-dependent inactivation of CACNA1C and regulates RYR2 calcium-release channel activity.
file:mouse/Calm2/Calm2-deep-research-falcon.md
Falcon synthesis highlights calmodulin regulation of L-type calcium channels, RyR2, and calcium exchangers as central channel-control roles.

Activates calmodulin-responsive kinases and phosphatases to propagate calcium-dependent signaling.

Molecular Function:

protein serine/threonine kinase activator activity

Directly Involved In:

calcineurin-mediated signaling

Cellular Locations:

cytosol

Supporting Evidence:

UniProtKB:P0DP27
Among the enzymes stimulated by the calmodulin-calcium complex are protein kinases and phosphatases.
file:mouse/Calm2/Calm2-deep-research-falcon.md
Falcon synthesis supports calmodulin activation of kinases and phosphatases as a major calcium-dependent signaling output.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000096

Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000119

Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12223552

Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels.

PMID:19855925

Structural analysis of the complex between calmodulin and full-length myelin basic protein, an intrinsically disordered molecule.

PMID:2469574

Calmodulin is required for cell-cycle progression during G1 and mitosis.

PMID:31628181

Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.

PMID:33199372

Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform 4, NCKX4.

file:mouse/Calm2/Calm2-deep-research-falcon.md

Falcon deep research summary for mouse Calm2

Calm2 encodes the same calmodulin protein sequence as the other mouse Calm loci, with gene-specific relevance largely driven by transcript abundance and expression context.
Falcon synthesis supports calmodulin as a four-EF-hand calcium sensor that regulates channels, exchangers, kinases, and phosphatases.

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(Calm2-deep-research-falcon.md)

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gene_info: Name=Calm2 {ECO:0000312|MGI:MGI:103250}; Synonyms=Cam2, CamC;
organism_full: Mus musculus (Mouse).
protein_family: Belongs to the calmodulin family. .
protein_domains: CALM/Myosin/TropC-like. (IPR050230); EF-hand-dom_pair. (IPR011992);
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P0DP27
Protein Description: RecName: Full=Calmodulin-2 {ECO:0000250|UniProtKB:P0DP24};
Gene Information: Name=Calm2 {ECO:0000312|MGI:MGI:103250}; Synonyms=Cam2, CamC;
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the calmodulin family. .
Key Domains: CALM/Myosin/TropC-like. (IPR050230); EF-hand-dom_pair. (IPR011992); EF_Hand_1_Ca_BS. (IPR018247); EF_hand_dom. (IPR002048); EF-hand_7 (PF13499)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Calm2" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'Calm2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene Calm2 (gene ID: Calm2, UniProt: P0DP27) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P0DP27
Protein Description: RecName: Full=Calmodulin-2 {ECO:0000250|UniProtKB:P0DP24};
Gene Information: Name=Calm2 {ECO:0000312|MGI:MGI:103250}; Synonyms=Cam2, CamC;
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the calmodulin family. .
Key Domains: CALM/Myosin/TropC-like. (IPR050230); EF-hand-dom_pair. (IPR011992); EF_Hand_1_Ca_BS. (IPR018247); EF_hand_dom. (IPR002048); EF-hand_7 (PF13499)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Calm2" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene Calm2 (gene ID: Calm2, UniProt: P0DP27) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive research report: Mus musculus Calm2 (UniProt P0DP27) / calmodulin-2

0) Target verification and scope control

Target identity (verified): The UniProt accession P0DP27 corresponds to mouse calmodulin-2 (Calm2), a canonical calmodulin (CaM) family protein. A critical complication is that in mammals multiple Calm/CALM genes encode an identical CaM protein sequence (mouse: Calm1/Calm2/Calm3; human: CALM1/2/3). Therefore:
- Protein-level mechanisms (Ca2+ sensing via EF-hands, bilobal switching, target binding) generally apply to the Calm2 protein product, because the protein sequence is the same across calmodulin genes. (badone2018calmodulinopathyfunctionaleffects pages 1-2, hussey2023calmodulinmutationsin pages 1-2)
- Gene-level statements (transcript abundance, gene-specific perturbation therapies) must be attributed to Calm2 specifically when evidence exists. (tsai2025enrichmentofmutant pages 6-10)

1) Key concepts and definitions (current understanding)

1.1 Calmodulin (CaM) as a Ca2+ sensor

Calmodulin is a ubiquitous, highly conserved Ca2+-binding signaling protein that translates intracellular Ca2+ fluctuations into altered activity of diverse target proteins across many pathways, including ion channels and kinases. (hussey2023calmodulinmutationsin pages 1-2, badone2018calmodulinopathyfunctionaleffects pages 1-2)

Size and architecture. CaM is described as a ~149-aa, ~17 kDa protein organized into two globular lobes (N- and C-lobes) connected by a flexible linker; each lobe contains two EF-hand helix–loop–helix motifs, giving a total of four Ca2+-binding sites. (badone2018calmodulinopathyfunctionaleffects pages 1-2, hussey2023calmodulinmutationsin pages 1-2)

1.2 EF-hand motifs and Ca2+-dependent conformational switching

EF-hands are helix–loop–helix Ca2+-binding modules that, upon Ca2+ binding, promote conformational opening of CaM lobes and exposure of methionine-rich hydrophobic pockets that engage target helices. (denesyuk2023canonicalstructuralbindingmodes pages 5-8)

A structural survey identifies Ca2+-binding loops at approximately residues 20–31, 56–67, 93–104, 129–140 in CaM. (denesyuk2023canonicalstructuralbindingmodes pages 1-5)

1.3 Bilobal functional partitioning (N-lobe vs C-lobe)

A key contemporary concept is that each lobe can act semi-independently to control different target behaviors, enabling CaM to decode Ca2+ signals in a lobe-specific manner. (hussey2023calmodulinmutationsin pages 2-4)

Quantitatively, a 2023 review reports distinct Ca2+ affinities for the two lobes, with tighter Ca2+ binding by the C-lobe (KD ≈ 2.4 µM) than the N-lobe (KD ≈ 16 µM). (hussey2023calmodulinmutationsin pages 1-2)

1.4 ApoCaM “pre-association” and target-binding motifs

Many CaM targets can bind apoCaM (Ca2+-free), which can pre-associate with targets prior to a Ca2+ rise; for example, apoCaM is described as bound to the IQ motif in the C-terminal tail of voltage-gated Ca2+ channels, supporting rapid Ca2+-dependent regulation. (hussey2023calmodulinmutationsin pages 2-4)

Target recognition often involves amphipathic helices with hydrophobic anchor residues. A systematic analysis of 35 CaM–target structures highlights common anchor-spacings/motif classes {1–10}, {1–11}, {1–13}, {1–14}, {1–16}, {1–17}, and proposes an additional {1–5} binding mode contributing to canonical binding. (denesyuk2023canonicalstructuralbindingmodes pages 1-5)

2) Molecular function, pathways, and cellular localization of Calm2 product

2.1 Primary molecular function

Mouse Calm2 encodes calmodulin, whose primary molecular function is Ca2+ binding (via four EF-hands) and Ca2+-dependent regulation of target proteins through direct protein–protein interaction, acting as a switchable Ca2+ sensor/effector module. (hussey2023calmodulinmutationsin pages 1-2, badone2018calmodulinopathyfunctionaleffects pages 1-2)

2.2 Cellular localization

Calmodulin is described as a major Ca2+ sensor acting in cytoplasmic and endoplasmic reticulum-associated contexts, and it can redistribute to the nucleus to modulate longer-term signaling outcomes (e.g., transcriptional programs). (long2025thecriticalrole pages 30-35, badone2018calmodulinopathyfunctionaleffects pages 1-2)

In mouse ventricular cardiomyocytes, CALM immunofluorescence shows a striated pattern consistent with enrichment along Z-lines, indicating organized subcellular localization in the contractile apparatus region. (tsai2025enrichmentofmutant pages 6-10)

2.3 Major signaling pathways and targets (validated, mechanistic)

Because calmodulin proteins are identical across Calm genes, the best-supported “Calm2 protein product” targets are typically described at the protein level:

(i) Voltage-gated Ca2+ channels (CaV1.2/L-type): Ca2+-dependent inactivation (CDI). CaM is a core regulator of L-type Ca2+ channels, and loss of Ca2+ sensing by mutant CaM is emphasized as a mechanism impairing CDI. (badone2018calmodulinopathyfunctionaleffects pages 10-11)

(ii) Ryanodine receptor 2 (RyR2): SR Ca2+ release regulation. Reviews of calmodulinopathy highlight RyR2 as a central CaM-modulated cardiac target implicated in arrhythmogenic Ca2+ handling when regulation is perturbed. (hussey2023calmodulinmutationsin pages 1-2)

(iii) Small conductance Ca2+-activated K+ (SK) channels. ApoCaM is described as pre-associated with SK channel cytosolic tails; SK channels can bind multiple CaMs (e.g., four per channel), supporting Ca2+-dependent gating control. (hussey2023calmodulinmutationsin pages 2-4)

(iv) CaM-activated kinases (e.g., CaMKII) and CaM-dependent signaling. Calmodulin regulates CaMKII-dependent pathways; broader CaM signaling is also linked to calcineurin-dependent signaling in multiple contexts. (tsai2025enrichmentofmutant pages 36-43, steil2020thecalmodulinredox pages 10-11)

(v) eEF2K activation (protein synthesis regulation). Structural/biochemical evidence highlights CaM as an allosteric activator of eukaryotic elongation factor 2 kinase (eEF2K), with strong dependence on CaM domain interactions (notably C-lobe sufficiency in some mechanistic experiments). (long2025thecriticalrole pages 30-35)

3) Recent developments and latest research (prioritize 2023–2024)

3.1 2023: Updated mechanistic synthesis of CaM regulation and calmodulinopathies

A 2023 review consolidates modern understanding of:
- Bilobal functional specialization (each lobe imparting distinct regulatory effects on channels), (hussey2023calmodulinmutationsin pages 2-4)
- apoCaM pre-association with canonical motifs (e.g., channel IQ motifs), enabling fast Ca2+-dependent feedback, (hussey2023calmodulinmutationsin pages 2-4)
- Quantitative lobe Ca2+ affinities (C-lobe tighter than N-lobe), supporting how CaM can decode Ca2+ signals over different dynamic ranges. (hussey2023calmodulinmutationsin pages 1-2)

These points are particularly relevant for functional annotation because they explain why calmodulin can act as both (a) a diffusible sensor and (b) a pre-docked regulatory subunit whose Ca2+-binding triggers rapid gating/enzymatic changes. (hussey2023calmodulinmutationsin pages 2-4, badone2018calmodulinopathyfunctionaleffects pages 1-2)

3.2 2023: Structural generalization of CaM–target binding modes

A 2023 analysis of 35 CaM–target complex structures provides an updated structural “parts list” for how CaM achieves promiscuous but specific binding, emphasizing:
- common hydrophobic-anchor motif classes ({1–10}, {1–14}, etc.),
- methionine-rich target-binding surfaces exposed upon Ca2+ binding,
- and an additional proposed {1–5} mode that can contribute to canonical binding geometry. (denesyuk2023canonicalstructuralbindingmodes pages 1-5, denesyuk2023canonicalstructuralbindingmodes pages 5-8)

This informs functional annotation by explaining how the same Calm2 protein can couple Ca2+ signals to many unrelated pathways through conserved physical recognition principles. (denesyuk2023canonicalstructuralbindingmodes pages 1-5)

3.3 2024: Gene-specific therapeutic strategy leveraging CALM gene redundancy (real-world translational implementation)

A major 2024 translational advance is proof-of-concept gene-specific antisense oligonucleotide (ASO) therapy for calmodulinopathies, explicitly exploiting that the three CALM genes encode identical protein.

In a Circulation 2024 study, a palmitoylated murine Calm1-targeting ASO depleted Calm1 transcript by ~90% in heart (with dose-dependent knockdown), while total CaM protein was not significantly altered because Calm2 and Calm3 transcripts increased (compensatory upregulation). (bortolin2024antisenseoligonucleotidetherapy pages 6-8, bortolin2024antisenseoligonucleotidetherapy pages 8-10)

Functionally, high-dose ASO strongly suppressed epinephrine+caffeine–induced bidirectional ventricular tachycardia in a Calm1N98S/+ mouse model (prevention in 11/12 mice at 50 mg/kg dosing). (bortolin2024antisenseoligonucleotidetherapy pages 6-8)

Although this is not a Calm2-targeted therapy, it is directly relevant to Calm2 functional annotation because it:
- demonstrates in vivo that gene-specific reduction of one Calm gene can preserve protein-level CaM function via redundancy, (bortolin2024antisenseoligonucleotidetherapy pages 8-10)
- and highlights the translational importance of understanding gene-level Calm expression balance (including Calm2). (bortolin2024antisenseoligonucleotidetherapy pages 6-8, bortolin2024antisenseoligonucleotidetherapy pages 8-10)

4) Current applications and real-world implementations

4.1 Precision therapy concept for calmodulinopathies

The ASO strategy described above is a concrete implementation of precision medicine for calmodulinopathy: selectively depleting the affected CALM gene’s transcript while maintaining total CaM protein via the other CALM genes. (bortolin2024antisenseoligonucleotidetherapy pages 1-3, bortolin2024antisenseoligonucleotidetherapy pages 8-10)

The work also provides quantitative design constraints: in mice, >~85% depletion was reported as needed to prevent severe arrhythmia phenotypes, revealing a steep non-linear relationship between transcript fraction and phenotype in this model. (bortolin2024antisenseoligonucleotidetherapy pages 6-8, bortolin2024antisenseoligonucleotidetherapy pages 10-12)

4.2 Functional annotation-relevant use cases in physiology and disease modeling

Calmodulin’s role in regulating CaV1.2 CDI and RyR2 places it at the center of excitation–contraction coupling and arrhythmia mechanisms (especially when Ca2+/CaM regulation is disrupted). (badone2018calmodulinopathyfunctionaleffects pages 10-11, hussey2023calmodulinmutationsin pages 1-2)

5) Mouse-specific evidence for Calm2 (gene-level) and phenotype-relevant context

5.1 Calm2 expression dominance in mouse heart

In mouse left ventricle, Calm2 is reported as the most abundant Calm transcript (≈ 41% of total Calm transcripts), compared with Calm3 (≈32%) and Calm1 (≈27%). (tsai2025enrichmentofmutant pages 6-10)

This is important because, while all three genes encode identical protein, gene-level regulation affects how a variant or gene-specific perturbation propagates to protein pools, particularly in tissues like heart where calmodulinopathy manifests strongly. (tsai2025enrichmentofmutant pages 6-10, hussey2023calmodulinmutationsin pages 1-2)

5.2 Limitations: Calm2-specific mouse knockout/variant phenotype literature

Within the retrieved evidence set, direct Calm2-specific mouse loss-of-function phenotypes were not found; many mechanistic in vivo phenotypes are demonstrated using Calm1 knock-in models while invoking protein-level equivalence across Calm genes. (tsai2020complexarrhythmiasyndrome pages 1-3, bortolin2024antisenseoligonucleotidetherapy pages 6-8)

Accordingly, the most defensible Calm2 functional annotation is:
- Protein-level function: canonical calmodulin biology (Ca2+ sensor/regulator). (hussey2023calmodulinmutationsin pages 1-2, badone2018calmodulinopathyfunctionaleffects pages 1-2)
- Gene-level context: Calm2 is a predominant transcript in mouse heart and is therefore likely a major contributor to total cardiac CaM pool. (tsai2025enrichmentofmutant pages 6-10)

6) Expert opinions and analysis from authoritative sources

Authoritative reviews emphasize that calmodulin’s broad regulatory reach is achieved by:
- apoCaM pre-association with targets enabling fast feedback,
- bilobal specialization enabling distinct modes of regulation,
- and conserved structural principles (hydrophobic anchors, methionine-rich pockets) enabling “promiscuous specificity.” (hussey2023calmodulinmutationsin pages 2-4, denesyuk2023canonicalstructuralbindingmodes pages 1-5, denesyuk2023canonicalstructuralbindingmodes pages 5-8)

In disease-focused expert synthesis, CaM mutations are interpreted to produce prominent cardiac phenotypes because they selectively disrupt Ca2+-dependent regulation of key cardiac targets such as CaV1.2 and RyR2, shifting action potential repolarization and/or intracellular Ca2+ handling stability. (hussey2023calmodulinmutationsin pages 1-2, badone2018calmodulinopathyfunctionaleffects pages 10-11)

7) Statistics and quantitative data (recent sources prioritized)

Key quantitative facts useful for functional annotation:
- Lobe-specific Ca2+ affinities: C-lobe KD ≈ 2.4 µM vs N-lobe KD ≈ 16 µM. (hussey2023calmodulinmutationsin pages 1-2)
- Ca2+-dependent complex tightness: structural analysis notes CaM can form very tight Ca2+-dependent complexes (Kd < 10^-7 M). (denesyuk2023canonicalstructuralbindingmodes pages 5-8)
- Mouse heart Calm transcript shares (LV): Calm2 ≈ 41%, Calm3 ≈ 32%, Calm1 ≈ 27%. (tsai2025enrichmentofmutant pages 6-10)
- 2024 ASO therapy (model/implementation metrics): ~90% Calm1 transcript depletion; prevention of inducible sustained biVT in 11/12 Calm1N98S/+ mice at 50 mg/kg; no significant change in total CaM protein in heart. (bortolin2024antisenseoligonucleotidetherapy pages 6-8, bortolin2024antisenseoligonucleotidetherapy pages 8-10)

8) Visual evidence (figures)

The 2023 review contains schematics useful for functional annotation:
- CaM domain architecture with EF-hand Ca2+ sites. (hussey2023calmodulinmutationsin media 7f5b83fd)
- Schematic of CaV1.2 regulation by CaM, including Ca2+-dependent inactivation (CDI) and how EF-hand mutations can disrupt this regulation. (hussey2023calmodulinmutationsin media cf2de50e)
- General mechanistic model for CaM regulation of targets that is applied in the review’s discussion of RyR2 regulation. (hussey2023calmodulinmutationsin media 8eac985e)

9) Summary functional annotation (for Calm2 / CaM)

Primary function: Ca2+-binding regulatory protein that couples intracellular Ca2+ signals to downstream effectors via Ca2+-dependent conformational switching and target binding. (hussey2023calmodulinmutationsin pages 1-2, badone2018calmodulinopathyfunctionaleffects pages 1-2)

Key mechanisms: bilobal EF-hand structure; lobe-specific Ca2+ affinities; apoCaM preassociation; target binding via IQ motifs and hydrophobic anchor motifs; Ca2+ binding exposes methionine-rich pockets enabling high-affinity target engagement. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 1-2, denesyuk2023canonicalstructuralbindingmodes pages 1-5, denesyuk2023canonicalstructuralbindingmodes pages 5-8)

Localization: cytosolic/ER-associated sensor with capacity for nuclear redistribution; in cardiomyocytes shows striated Z-line-associated pattern. (badone2018calmodulinopathyfunctionaleffects pages 1-2, tsai2025enrichmentofmutant pages 6-10)

Major pathways/targets: CaV1.2 (CDI), RyR2, SK channels, CaMKII signaling, and eEF2K activation. (badone2018calmodulinopathyfunctionaleffects pages 10-11, hussey2023calmodulinmutationsin pages 2-4, long2025thecriticalrole pages 30-35, hussey2023calmodulinmutationsin pages 1-2)

Mouse gene-level context: Calm2 is a predominant cardiac Calm transcript in LV (~41%), which is relevant for interpreting gene-specific perturbations/therapies even though CaM protein sequence is shared across Calm genes. (tsai2025enrichmentofmutant pages 6-10)

Key sources (with dates and URLs)

Hussey JW, Limpitikul WB, Dick IE. Calmodulin Mutations in Human Disease. Channels (Jan 2023). https://doi.org/10.1080/19336950.2023.2165278 (hussey2023calmodulinmutationsin pages 1-2, hussey2023calmodulinmutationsin pages 2-4)
Denesyuk AI et al. Canonical structural-binding modes in the calmodulin–target protein complexes. J Biomol Struct Dyn (Sep 2023). https://doi.org/10.1080/07391102.2022.2123391 (denesyuk2023canonicalstructuralbindingmodes pages 1-5, denesyuk2023canonicalstructuralbindingmodes pages 5-8)
Bortolin RH et al. Antisense Oligonucleotide Therapy for Calmodulinopathy. Circulation (Oct 2024). https://doi.org/10.1161/circulationaha.123.068111 (bortolin2024antisenseoligonucleotidetherapy pages 6-8, bortolin2024antisenseoligonucleotidetherapy pages 8-10, bortolin2024antisenseoligonucleotidetherapy pages 1-3)
Tsai W-C et al. Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy. JCI Insight (Jul 2025). https://doi.org/10.1172/jci.insight.185524 (used primarily for mouse Calm2 transcript proportion and localization imaging context) (tsai2025enrichmentofmutant pages 6-10)

Annotation area	Key fact for mouse Calm2 / calmodulin-2	Evidence / quantitative detail
Identity and architecture	Calm2 (mouse; UniProt P0DP27) encodes calmodulin, an approximately 149-aa, ~17 kDa highly conserved bilobal Ca2+ sensor; each lobe contains two EF-hand motifs for a total of 4 Ca2+-binding sites. Because mouse Calm1/Calm2/Calm3 encode the same CaM protein sequence, most protein-level mechanism data apply to Calm2 protein product, while gene-level expression can differ. (badone2018calmodulinopathyfunctionaleffects pages 1-2, hussey2023calmodulinmutationsin pages 1-2)	N- and C-lobes are linked by a flexible helix/linker; EF-hand loops are located at residues 20-31, 56-67, 93-104, 129-140 in structural analyses. (denesyuk2023canonicalstructuralbindingmodes pages 1-5)
Ca2+ affinities	The two lobes have distinct Ca2+ affinities; the C-lobe binds Ca2+ more tightly than the N-lobe, supporting lobe-specific decoding of Ca2+ signals. (hussey2023calmodulinmutationsin pages 1-2)	Approximate dissociation constants reported in a 2023 review: C-lobe KD ≈ 2.4 µM versus N-lobe KD ≈ 16 µM. Some disease-associated EF-hand mutations preserve apoCaM structure while selectively impairing Ca2+-bound regulation. (hussey2023calmodulinmutationsin pages 1-2, hussey2023calmodulinmutationsin pages 2-4)
Target-recognition rules	CaM recognizes many targets through canonical CaM-binding motifs, including IQ motifs and amphipathic helices carrying hydrophobic anchor residues. ApoCaM can pre-associate with targets before Ca2+ rises. (hussey2023calmodulinmutationsin pages 2-4, denesyuk2023canonicalstructuralbindingmodes pages 5-8)	Structural surveys of 35 complexes found common anchor spacings of {1-10}, {1-11}, {1-13}, {1-14}, {1-16}, {1-17}, plus an added {1-5} mode; Ca2+ binding opens the lobes and exposes methionine-rich hydrophobic pockets. Ca2+-dependent complexes can be very tight (KD < 10^-7 M). (denesyuk2023canonicalstructuralbindingmodes pages 1-5, denesyuk2023canonicalstructuralbindingmodes pages 5-8, denesyuk2023canonicalstructuralbindingmodes pages 14-16)
Major validated targets / pathways	Calmodulin regulates multiple validated signaling/excitability targets relevant to mammalian physiology: CaV1.2/L-type Ca2+ channels (especially Ca2+-dependent inactivation, CDI), RyR2, SK channels, and CaM-activated kinases such as CaMKII and eEF2K. (badone2018calmodulinopathyfunctionaleffects pages 11-12, long2025thecriticalrole pages 30-35, hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin media 7f5b83fd)	Lobe-specific regulation is a recurring principle: apoCaM is pre-bound to channel tails such as IQ motifs; altered Ca2+/CaM control can weaken CaV1.2 CDI, destabilize RyR2, and reduce SK activation in pathogenic settings. eEF2K activation is strongly dependent on CaM, with prominent contribution from the C-terminal lobe in structural/biochemical studies. (tsai2020complexarrhythmiasyndrome pages 1-3, long2025thecriticalrole pages 30-35, hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin media 7f5b83fd)
Cellular localization	Calmodulin acts mainly as a cytosolic and endoplasmic reticulum-associated Ca2+ sensor, but it can also translocate to the nucleus to influence transcriptional signaling. (badone2018calmodulinopathyfunctionaleffects pages 11-12, long2025thecriticalrole pages 30-35, badone2018calmodulinopathyfunctionaleffects pages 1-2)	In mouse cardiomyocytes, CALM immunofluorescence shows a striated pattern enriched along Z-lines, consistent with organized sarcomeric localization in heart muscle. (tsai2025enrichmentofmutant pages 6-10)
Mouse heart transcript proportions	In mouse heart, Calm2 is the predominant Calm transcript, supporting the relevance of gene-specific annotation even though all three genes encode identical protein. (tsai2025enrichmentofmutant pages 6-10)	In wild-type mouse left ventricle, reported transcript shares were approximately Calm2 41%, Calm3 32%, Calm1 27% of total Calm transcripts; atria showed even higher Calm2:Calm1 and Calm2:Calm3 ratios than ventricles. (tsai2025enrichmentofmutant pages 6-10)

Table: This table compiles compact, citation-backed facts needed for functional annotation of mouse Calm2/calmodulin-2, covering structure, Ca2+ binding, target-recognition rules, major pathways, localization, and mouse cardiac expression proportions.

References

(badone2018calmodulinopathyfunctionaleffects pages 1-2): Beatrice Badone, Carlotta Ronchi, Maria-Christina Kotta, Luca Sala, Alice Ghidoni, Lia Crotti, and Antonio Zaza. Calmodulinopathy: functional effects of calm mutations and their relationship with clinical phenotypes. Frontiers in Cardiovascular Medicine, Dec 2018. URL: https://doi.org/10.3389/fcvm.2018.00176, doi:10.3389/fcvm.2018.00176. This article has 39 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 1-2): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(tsai2025enrichmentofmutant pages 6-10): Wen-Chin Tsai, Chiu-Fen Yang, Shu-Yu Lin, Suh-Yuen Liang, Wei-Chung Tsai, Shuai Guo, Xiaochun Li, Susan Ofner, Kai-Chien Yang, Tzu-Ching Meng, Peng-Sheng Chen, and Michael Rubart. Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy. JCI Insight, Jul 2025. URL: https://doi.org/10.1172/jci.insight.185524, doi:10.1172/jci.insight.185524. This article has 1 citations and is from a domain leading peer-reviewed journal.
(denesyuk2023canonicalstructuralbindingmodes pages 5-8): Alexander I. Denesyuk, Sergei E. Permyakov, Eugene A. Permyakov, Mark S. Johnson, Konstantin Denessiouk, and Vladimir N. Uversky. Canonical structural-binding modes in the calmodulin–target protein complexes. Journal of Biomolecular Structure and Dynamics, 41:7582-7594, Sep 2023. URL: https://doi.org/10.1080/07391102.2022.2123391, doi:10.1080/07391102.2022.2123391. This article has 6 citations and is from a peer-reviewed journal.
(denesyuk2023canonicalstructuralbindingmodes pages 1-5): Alexander I. Denesyuk, Sergei E. Permyakov, Eugene A. Permyakov, Mark S. Johnson, Konstantin Denessiouk, and Vladimir N. Uversky. Canonical structural-binding modes in the calmodulin–target protein complexes. Journal of Biomolecular Structure and Dynamics, 41:7582-7594, Sep 2023. URL: https://doi.org/10.1080/07391102.2022.2123391, doi:10.1080/07391102.2022.2123391. This article has 6 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 2-4): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(long2025thecriticalrole pages 30-35): Kimberly J. Long, Luke S. Browning, Andrea Piserchio, Eta A. Isiorho, Mohamed I. Gadallah, Jomai Douangvilay, Elizabeth Y. Wang, Justin K. Kalugin, Jennifer S. Brodbelt, Ranajeet Ghose, and Kevin N. Dalby. The critical role of the c-terminal lobe of calmodulin in activating eukaryotic elongation factor 2 kinase. bioRxiv, May 2025. URL: https://doi.org/10.1101/2025.05.13.653565, doi:10.1101/2025.05.13.653565. This article has 1 citations.
(badone2018calmodulinopathyfunctionaleffects pages 10-11): Beatrice Badone, Carlotta Ronchi, Maria-Christina Kotta, Luca Sala, Alice Ghidoni, Lia Crotti, and Antonio Zaza. Calmodulinopathy: functional effects of calm mutations and their relationship with clinical phenotypes. Frontiers in Cardiovascular Medicine, Dec 2018. URL: https://doi.org/10.3389/fcvm.2018.00176, doi:10.3389/fcvm.2018.00176. This article has 39 citations and is from a peer-reviewed journal.
(tsai2025enrichmentofmutant pages 36-43): Wen-Chin Tsai, Chiu-Fen Yang, Shu-Yu Lin, Suh-Yuen Liang, Wei-Chung Tsai, Shuai Guo, Xiaochun Li, Susan Ofner, Kai-Chien Yang, Tzu-Ching Meng, Peng-Sheng Chen, and Michael Rubart. Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy. JCI Insight, Jul 2025. URL: https://doi.org/10.1172/jci.insight.185524, doi:10.1172/jci.insight.185524. This article has 1 citations and is from a domain leading peer-reviewed journal.
(steil2020thecalmodulinredox pages 10-11): Alex W. Steil, Jacob W. Kailing, Cade J. Armstrong, Daniel G. Walgenbach, and Jennifer C. Klein. The calmodulin redox sensor controls myogenesis. PLoS ONE, 15:e0239047, Sep 2020. URL: https://doi.org/10.1371/journal.pone.0239047, doi:10.1371/journal.pone.0239047. This article has 5 citations and is from a peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 6-8): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 8-10): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 1-3): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 10-12): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.
(tsai2020complexarrhythmiasyndrome pages 1-3): Wen-Chin Tsai, Shuai Guo, Michael A. Olaopa, Loren J. Field, Jin Yang, Changyu Shen, Ching-Pin Chang, Peng-Sheng Chen, and Michael Rubart. Complex arrhythmia syndrome in a knock-in mouse model carrier of the n98s calm1 mutation. Circulation, 142:1937-1955, Nov 2020. URL: https://doi.org/10.1161/circulationaha.120.046450, doi:10.1161/circulationaha.120.046450. This article has 23 citations and is from a highest quality peer-reviewed journal.
(hussey2023calmodulinmutationsin media 7f5b83fd): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin media cf2de50e): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin media 8eac985e): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(denesyuk2023canonicalstructuralbindingmodes pages 14-16): Alexander I. Denesyuk, Sergei E. Permyakov, Eugene A. Permyakov, Mark S. Johnson, Konstantin Denessiouk, and Vladimir N. Uversky. Canonical structural-binding modes in the calmodulin–target protein complexes. Journal of Biomolecular Structure and Dynamics, 41:7582-7594, Sep 2023. URL: https://doi.org/10.1080/07391102.2022.2123391, doi:10.1080/07391102.2022.2123391. This article has 6 citations and is from a peer-reviewed journal.
(badone2018calmodulinopathyfunctionaleffects pages 11-12): Beatrice Badone, Carlotta Ronchi, Maria-Christina Kotta, Luca Sala, Alice Ghidoni, Lia Crotti, and Antonio Zaza. Calmodulinopathy: functional effects of calm mutations and their relationship with clinical phenotypes. Frontiers in Cardiovascular Medicine, Dec 2018. URL: https://doi.org/10.3389/fcvm.2018.00176, doi:10.3389/fcvm.2018.00176. This article has 39 citations and is from a peer-reviewed journal.

Citations

tsai2025enrichmentofmutant pages 6-10
denesyuk2023canonicalstructuralbindingmodes pages 5-8
denesyuk2023canonicalstructuralbindingmodes pages 1-5
hussey2023calmodulinmutationsin pages 2-4
hussey2023calmodulinmutationsin pages 1-2
badone2018calmodulinopathyfunctionaleffects pages 10-11
long2025thecriticalrole pages 30-35
bortolin2024antisenseoligonucleotidetherapy pages 6-8
bortolin2024antisenseoligonucleotidetherapy pages 8-10
badone2018calmodulinopathyfunctionaleffects pages 1-2
tsai2025enrichmentofmutant pages 36-43
steil2020thecalmodulinredox pages 10-11
bortolin2024antisenseoligonucleotidetherapy pages 1-3
bortolin2024antisenseoligonucleotidetherapy pages 10-12
tsai2020complexarrhythmiasyndrome pages 1-3
denesyuk2023canonicalstructuralbindingmodes pages 14-16
badone2018calmodulinopathyfunctionaleffects pages 11-12
https://doi.org/10.1080/19336950.2023.2165278
https://doi.org/10.1080/07391102.2022.2123391
https://doi.org/10.1161/circulationaha.123.068111
https://doi.org/10.1172/jci.insight.185524
https://doi.org/10.3389/fcvm.2018.00176,
https://doi.org/10.1080/19336950.2023.2165278,
https://doi.org/10.1172/jci.insight.185524,
https://doi.org/10.1080/07391102.2022.2123391,
https://doi.org/10.1101/2025.05.13.653565,
https://doi.org/10.1371/journal.pone.0239047,
https://doi.org/10.1161/circulationaha.123.068111,
https://doi.org/10.1161/circulationaha.120.046450,

Notes

(Calm2-notes.md)

Calm2 notes

2026-03-19 ISO-focused review

Calm1, Calm2, and Calm3 encode identical calmodulin proteins in mammals, but the loci differ in regulation and expression context, so locus-specific functional claims need stronger support than generic calmodulin biochemistry. [file:projects/ISO.md, "Calm1, Calm2, and Calm3 encode identical protein sequences in many mammals but differ in UTR regulation, tissue expression patterns, and potentially in interaction partners."]
The local GOA for mouse Calm2 mixes ISO transfers from human CALM2 (UniProtKB:P0DP24) with transfers from rat RGD:2257, RGD:2258, and RGD:2259. Those rat IDs are Calm1, Calm2, and Calm3 respectively, so the source gene is not consistently the strict Calm2 ortholog. [file:mouse/Calm2/Calm2-goa.tsv, "ISO rows for Calm2 cite UniProtKB:P0DP24 and RGD:2257/2258/2259 as sources."] RGD REST lookups used during review: https://rest.rgd.mcw.edu/rgdws/genes/2257, https://rest.rgd.mcw.edu/rgdws/genes/2258, https://rest.rgd.mcw.edu/rgdws/genes/2259.
The mouse UniProt entry supports broad family-conserved calmodulin functions: calcium-dependent control of enzymes and ion channels, CACNA1C/RYR2 regulation, and centrosome/cytokinesis biology. [file:mouse/Calm2/Calm2-uniprot.txt, "Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding."] [file:mouse/Calm2/Calm2-uniprot.txt, "Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis."]
Direct mouse evidence for the Calm2 locus is strongest for synaptic endocytosis: Calm2 knockout mice impaired slow, rapid, and bulk endocytosis at calyx and hippocampal synapses. This supports specialized presynaptic annotations more strongly than the rat-paralog ISO transfers do. [PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses., "We generated ... calmodulin (calmodulin 2 gene) knock-out mice ... knock-outs inhibited slow, rapid and bulk endocytosis."]
Direct mouse evidence also supports calcium-dependent binding to NCKX4 and suppression of stimulated exchanger activity, which justifies specialized transporter-regulatory annotations but not generic membrane or vesicle localization. [PMID:33199372 Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform 4, NCKX4., "Calmodulin binding to NCKX4 was demonstrated in extracts from mouse brain ... coexpression of wild-type calmodulin ... suppressed NCKX4 activation in a time-dependent manner."]
General calmodulin evidence still supports retaining core calcium-sensor and mitotic functions at the gene-product level. [PMID:2469574 Calmodulin is required for cell-cycle progression during G1 and mitosis., "Progression through G1 and mitosis was affected by changes in CaM levels."]
Myelin association is plausible for calmodulin through MBP binding, but this is still specialized context and not a reason to accept every paralog-derived myelin ISO transfer as core Calm2 biology. [PMID:19855925 Structural analysis of the complex between calmodulin and full-length myelin basic protein, an intrinsically disordered molecule., "CaM and MBP colocalize in myelin sheaths."]

Working curation rule

Keep broad human-CALM2 ISO terms when they describe conserved calmodulin biochemistry or well-established channel/cell-cycle roles.
Downgrade rat-source ISO terms when they look like paralog bleed-through across Calm1/2/3 or when they overstate specialized neuronal localizations for the individual Calm2 locus.

📄 View Raw YAML

id: P0DP27
gene_symbol: Calm2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: 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.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: file:mouse/Calm2/Calm2-deep-research-falcon.md
      supporting_text: Falcon synthesis supports Calm2 as a canonical four-EF-hand
        calcium sensor and notes that Calm1/2/3 encode identical calmodulin proteins.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Nuclear localization in some contexts
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulates RyR-mediated calcium release from SR
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005513
    label: detection of calcium ion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core calcium sensing function
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Centrosomal localization for cell division
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Myelin sheath localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cell cycle regulation at G2/M transition
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Spindle pole localization during mitosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Spindle localization for cell division
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Endocytosis regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0051649
    label: establishment of localization in cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Intracellular localization establishment
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Presynaptic enrichment is plausible for calmodulin but represents specialized
      neuronal context rather than a universal Calm2 localization.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0150034
    label: distal axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Distal axon localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Chromatin association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0001975
    label: response to amphetamine
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Amphetamine response in neurons
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0002027
    label: regulation of heart rate
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Heart-rate physiology is a downstream tissue-level consequence of calmodulin ion-channel
      regulation, not the primary molecular function of Calm2.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005246
    label: calcium channel regulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulates L-type calcium channels and ryanodine receptors
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005513
    label: detection of calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Core calcium sensing function
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Nuclear localization in some contexts
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Centrosomal localization for cell division
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Soluble cytosolic protein
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005876
    label: spindle microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Spindle microtubule association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0008179
    label: adenylate cyclase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Binds adenylate cyclase
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010856
    label: adenylate cyclase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Activates adenylate cyclase for cAMP signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulates RyR-mediated calcium release from SR
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010881
    label: regulation of cardiac muscle contraction by regulation of the release of
      sequestered calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cardiac calcium-induced calcium release is a tissue-specific physiological context
      downstream of calmodulin channel regulation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0016240
    label: autophagosome membrane docking
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Autophagosome docking regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0019855
    label: calcium channel inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Inhibits IP3 receptors and certain calcium channels
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Binds CaMK family and other protein kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Parent binding term for diverse calmodulin-recognition motifs; too generic
      to capture the relevant interactions precisely.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0030017
    label: sarcomere
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Sarcomere localization in muscle
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0030235
    label: nitric-oxide synthase regulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulation of nitric-oxide synthases is plausible for calmodulin proteins
      but is better treated as specialized, non-core biology for Calm2.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Neuronal growth cone localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Synaptic vesicle localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0031432
    label: titin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Titin binding in muscle
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0031800
    label: type 3 metabotropic glutamate receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: mGluR3 binding in neurons
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Mitochondrial membrane association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0032465
    label: regulation of cytokinesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cytokinesis regulation with CP110 and centrin
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0034704
    label: calcium channel complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Component of calcium channel complexes
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0035458
    label: cellular response to interferon-beta
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Interferon-beta response
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Myelin sheath localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Activates CaMKII and other calcium-dependent kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0043548
    label: phosphatidylinositol 3-kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: PI3K binding for signaling
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Binds ion channels and transporters
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: JAK-STAT pathway regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0048306
    label: calcium-dependent protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Calcium-dependent target protein binding
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0050998
    label: nitric-oxide synthase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Binding to nitric-oxide synthases is plausible but represents specialized
      signaling context rather than a core Calm2 function.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0051412
    label: response to corticosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Corticosterone response
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Response to calcium ion
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0055117
    label: regulation of cardiac muscle contraction
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cardiac contraction is a downstream tissue-level process; the direct supported
      function is calcium/channel regulation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0071346
    label: cellular response to type II interferon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Interferon-gamma response
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0072542
    label: protein phosphatase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Activates calcineurin (PP2B) phosphatase
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0098685
    label: Schaffer collateral - CA1 synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Hippocampal synapse localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0098901
    label: regulation of cardiac muscle cell action potential
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cardiac action potential regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Presynaptic localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0099524
    label: postsynaptic cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Postsynaptic localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0140056
    label: organelle localization by membrane tethering
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Organelle membrane tethering
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1900242
    label: regulation of synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Synaptic vesicle endocytosis regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1901844
    label: regulation of cell communication by electrical coupling involved in cardiac
      conduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cardiac electrical coupling regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Catalytic complex is too generic to be useful and adds no mechanistic
      precision beyond more specific binding and channel-complex terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:1990456
    label: mitochondrion-endoplasmic reticulum membrane tethering
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ER-mitochondria contact regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:2000300
    label: regulation of synaptic vesicle exocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Synaptic vesicle exocytosis regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0060315
    label: negative regulation of ryanodine-sensitive calcium-release channel activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Inhibits ryanodine receptor under certain conditions
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer reflects specialized context rather than
      a Calm2 core role
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Spindle pole localization during mitosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0002027
    label: regulation of heart rate
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Heart-rate physiology is a downstream tissue-level consequence of calmodulin ion-channel
      regulation, not the primary molecular function of Calm2.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005246
    label: calcium channel regulator activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Regulates L-type calcium channels and ryanodine receptors
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005513
    label: detection of calcium ion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Core calcium sensing function
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Nuclear localization is plausible for calmodulin but rat paralog transfers
      do not justify treating it as a Calm2-specific core localization.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer reflects specialized context rather than
      a Calm2 core role
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Centrosomal localization for cell division
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005876
    label: spindle microtubule
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Spindle microtubule association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0008179
    label: adenylate cyclase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Calmodulin directly binds calmodulin-responsive adenylate cyclases, a
      broadly conserved signaling interaction consistent with the identical CALM proteins.
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010856
    label: adenylate cyclase activator activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Activates adenylate cyclase for cAMP signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Regulates RyR-mediated calcium release from SR
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0010881
    label: regulation of cardiac muscle contraction by regulation of the release of
      sequestered calcium ion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cardiac calcium-induced calcium release is a tissue-specific physiological context
      downstream of calmodulin channel regulation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0019855
    label: calcium channel inhibitor activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Inhibits IP3 receptors and certain calcium channels
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Binds CaMK family and other protein kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: This parent binding term is too generic, and the rat-source ISO transfer
      does not add a Calm2-specific mechanistic claim.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general and supported only by paralog-sensitive ISO transfer
- term:
    id: GO:0030017
    label: sarcomere
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Sarcomere localization in muscle
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0030235
    label: nitric-oxide synthase regulator activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Specialized interaction inferred from paralog-sensitive ISO transfer
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0031432
    label: titin binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Titin binding in muscle
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0031800
    label: type 3 metabotropic glutamate receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Specific metabotropic glutamate receptor binding is not established directly
      for mouse Calm2 and the supporting ISO source is a rat paralog family transfer.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Mitochondrial membrane localization appears in all three rat calmodulin
      paralogs and is better treated as contextual, non-core localization for mouse
      Calm2.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0032465
    label: regulation of cytokinesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cytokinesis regulation with CP110 and centrin
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0034704
    label: calcium channel complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Component of calcium channel complexes
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Activates CaMKII and other calcium-dependent kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0043548
    label: phosphatidylinositol 3-kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: PI3K binding is a specific interaction claim not resolved cleanly for
      mouse Calm2 by rat paralog transfer.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core interaction
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Binds ion channels and transporters
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0048306
    label: calcium-dependent protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Calcium-dependent target protein binding
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0050998
    label: nitric-oxide synthase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Specialized interaction inferred from paralog-sensitive ISO transfer
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Response to calcium ion
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0055117
    label: regulation of cardiac muscle contraction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cardiac contraction is a downstream tissue-level process; the direct supported
      function is calcium/channel regulation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0072542
    label: protein phosphatase activator activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Activates calcineurin (PP2B) phosphatase
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0098685
    label: Schaffer collateral - CA1 synapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: This hippocampal synapse annotation is shared across rat calmodulin paralogs
      and is too context-specific to transfer cleanly onto the mouse Calm2 locus.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Presynaptic cytosol localization from rat paralog transfer is too source-ambiguous
      for a standalone ISO claim on mouse Calm2.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:0099524
    label: postsynaptic cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Postsynaptic cytosol localization from rat paralog transfer is too source-ambiguous
      for a standalone ISO claim on mouse Calm2.
    action: KEEP_AS_NON_CORE
    reason: Paralog-sensitive ISO transfer supports only specialized, non-core localization
- term:
    id: GO:1901844
    label: regulation of cell communication by electrical coupling involved in cardiac
      conduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Specialized physiological context rather than core Calm2 biochemistry
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Catalytic complex is too generic to be useful and adds no mechanistic
      precision beyond more specific binding and channel-complex terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0141110
    label: transporter inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:33199372
  review:
    summary: Calmodulin suppresses stimulated NCKX4 activity, supporting transporter
      inhibitor activity in a specific exchanger context.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized transporter-regulatory role
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient
        calmodulin mutant, suppressed NCKX4 activation in a time-dependent manner
- term:
    id: GO:0044305
    label: calyx of Held
  evidence_type: IMP
  original_reference_id: PMID:31628181
  review:
    summary: The study was performed at the calyx of Held and shows a specialized
      neuronal context for Calm2-dependent endocytosis.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal localization
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: We found that these knock-outs inhibited slow (∼10-30 s) and
        rapid (<∼3 s) endocytosis at large calyx-type calyces
- term:
    id: GO:0044305
    label: calyx of Held
  evidence_type: IDA
  original_reference_id: PMID:31628181
  review:
    summary: Localization to the calyx of Held is experimentally supported but represents
      a specialized neuronal compartment.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal localization
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: We found that these knock-outs inhibited slow (∼10-30 s) and
        rapid (<∼3 s) endocytosis at large calyx-type calyces
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: IMP
  original_reference_id: PMID:31628181
  review:
    summary: Calm2 knockout mice show presynaptic defects at calyx and hippocampal
      synapses, supporting a real but specialized presynaptic role.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: We found that these knock-outs inhibited slow (∼10-30 s) and
        rapid (<∼3 s) endocytosis at large calyx-type calyces
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: IDA
  original_reference_id: PMID:31628181
  review:
    summary: Experiments at calyx and hippocampal synapses support presynaptic cytosol
      localization, but this remains specialized neuronal biology rather than a core
      Calm2 localization.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal localization
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: We found that these knock-outs inhibited slow (∼10-30 s) and
        rapid (<∼3 s) endocytosis at large calyx-type calyces
- term:
    id: GO:0140238
    label: presynaptic endocytosis
  evidence_type: IMP
  original_reference_id: PMID:31628181
  review:
    summary: Calm2 knockout impairs calcium-stimulated synaptic endocytosis, supporting
      a genuine but specialized role in presynaptic endocytosis.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: 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
- term:
    id: GO:0140238
    label: presynaptic endocytosis
  evidence_type: IDA
  original_reference_id: PMID:31628181
  review:
    summary: The synaptic physiology study supports presynaptic endocytic involvement,
      but this is a specialized synaptic role rather than a core calmodulin function.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized neuronal function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33199372
  review:
    summary: The NCKX4 study shows a specific calcium-dependent interaction, but protein
      binding is too generic to retain as an informative molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: Calmodulin binding to NCKX4 was demonstrated in extracts from
        mouse brain and in transfected HEK293 cells
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33199372
  review:
    summary: This study examined calmodulin bound to a membrane transporter; it does
      not establish Calm2 as a stable membrane component.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotated localization derived from interaction context rather than
      stable residence
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: 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
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IDA
  original_reference_id: PMID:33199372
  review:
    summary: Association with transporter-containing fractions does not justify a
      general vesicle localization for Calm2.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotated localization derived from interaction context rather than
      stable residence
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: Calmodulin binding to NCKX4 was demonstrated in extracts from
        mouse brain and in transfected HEK293 cells
- term:
    id: GO:0048306
    label: calcium-dependent protein binding
  evidence_type: IPI
  original_reference_id: PMID:33199372
  review:
    summary: Direct interaction with NCKX4 supports the core calmodulin property of
      calcium-dependent binding to target proteins.
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: 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
- term:
    id: GO:0050848
    label: regulation of calcium-mediated signaling
  evidence_type: IGI
  original_reference_id: PMID:33199372
  review:
    summary: Calmodulin is a central calcium sensor, and NCKX4 genetic interaction
      data support a real role in regulating calcium-mediated signaling.
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: 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
- term:
    id: GO:1905913
    label: negative regulation of calcium ion export across plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:33199372
  review:
    summary: The NCKX4 study supports inhibition of calcium export across the plasma
      membrane in a specific transporter context, not a universal Calm2 role.
    action: KEEP_AS_NON_CORE
    reason: Direct mouse evidence supports a specialized transporter-regulatory role
    supported_by:
    - reference_id: PMID:33199372
      supporting_text: coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient
        calmodulin mutant, suppressed NCKX4 activation in a time-dependent manner
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: IDA
  original_reference_id: PMID:19855925
  review:
    summary: Myelin sheath localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:19855925
      supporting_text: CaM and MBP colocalize in myelin sheaths.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019855
    label: calcium channel inhibitor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Inhibits IP3 receptors and certain calcium channels
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0060315
    label: negative regulation of ryanodine-sensitive calcium-release channel activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Inhibits ryanodine receptor under certain conditions
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0008076
    label: voltage-gated potassium channel complex
  evidence_type: IGI
  original_reference_id: PMID:12223552
  review:
    summary: KCNQ channel complex component
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:12223552
      supporting_text: Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels.
- term:
    id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  evidence_type: IDA
  original_reference_id: PMID:2469574
  review:
    summary: Cell cycle regulation at G2/M transition
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:2469574
      supporting_text: Calmodulin is required for cell-cycle progression during G1
        and mitosis.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: TAS
  original_reference_id: PMID:2469574
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: PMID:2469574
      supporting_text: Calmodulin is required for cell-cycle progression during G1
        and mitosis.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-rat orthologs
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-human orthologs
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12223552
  title: Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels.
  findings: []
- id: PMID:19855925
  title: Structural analysis of the complex between calmodulin and full-length myelin
    basic protein, an intrinsically disordered molecule.
  findings: []
- id: PMID:2469574
  title: Calmodulin is required for cell-cycle progression during G1 and mitosis.
  findings: []
- id: PMID:31628181
  title: Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated
    Endocytosis at Synapses.
  findings: []
- id: PMID:33199372
  title: Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform
    4, NCKX4.
  findings: []
- id: file:mouse/Calm2/Calm2-deep-research-falcon.md
  title: Falcon deep research summary for mouse Calm2
  findings:
  - statement: Calm2 encodes the same calmodulin protein sequence as the other mouse
      Calm loci, with gene-specific relevance largely driven by transcript abundance
      and expression context.
  - statement: Falcon synthesis supports calmodulin as a four-EF-hand calcium sensor
      that regulates channels, exchangers, kinases, and phosphatases.
core_functions:
- description: Primary intracellular calcium sensor that binds calcium through four
    EF-hand motifs and converts calcium binding into target regulation.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0005513
    label: detection of calcium ion
  supported_by:
  - reference_id: UniProtKB:P0DP27
    supporting_text: Calmodulin acts as part of a calcium signal transduction pathway
      by mediating the control of a large number of enzymes, ion channels, aquaporins
      and other proteins through calcium-binding.
  - reference_id: file:mouse/Calm2/Calm2-deep-research-falcon.md
    supporting_text: Falcon synthesis supports Calm2 as a canonical four-EF-hand
      calcium sensor and notes that Calm1/2/3 encode identical calmodulin proteins.
- description: Regulates calcium channels and exchangers, including ryanodine receptors
    and NCKX4, to tune calcium release and calcium export.
  molecular_function:
    id: GO:0005246
    label: calcium channel regulator activity
  directly_involved_in:
  - id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  - id: GO:0060315
    label: negative regulation of ryanodine-sensitive calcium-release channel activity
  supported_by:
  - reference_id: PMID:33199372
    supporting_text: When purinergic stimulation of NCKX4 was examined in these cells,
      coexpression of wild-type calmodulin, but not a Ca2+ binding-deficient calmodulin
      mutant, suppressed NCKX4 activation in a time-dependent manner
  - reference_id: UniProtKB:P0DP27
    supporting_text: Mediates calcium-dependent inactivation of CACNA1C and regulates
      RYR2 calcium-release channel activity.
  - reference_id: file:mouse/Calm2/Calm2-deep-research-falcon.md
    supporting_text: Falcon synthesis highlights calmodulin regulation of L-type
      calcium channels, RyR2, and calcium exchangers as central channel-control roles.
  in_complex:
    id: GO:0034704
    label: calcium channel complex
- description: Activates calmodulin-responsive kinases and phosphatases to propagate
    calcium-dependent signaling.
  molecular_function:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0097720
    label: calcineurin-mediated signaling
  supported_by:
  - reference_id: UniProtKB:P0DP27
    supporting_text: Among the enzymes stimulated by the calmodulin-calcium complex
      are protein kinases and phosphatases.
  - reference_id: file:mouse/Calm2/Calm2-deep-research-falcon.md
    supporting_text: Falcon synthesis supports calmodulin activation of kinases and
      phosphatases as a major calcium-dependent signaling output.
proposed_new_terms: []
suggested_questions:
- question: Which mouse calmodulin locus supplies the calmodulin protein detected
    at specialized neuronal compartments where rat Calm1/2/3 currently share the same
    annotations?
- question: 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?
suggested_experiments:
- description: 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.
  experiment_type: Endogenous tagging and quantitative proteomics
- description: 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.
  experiment_type: Genetic rescue under native or promoter-swapped expression

Calm2

Gene Description

Existing Annotations Review

Core Functions

Primary intracellular calcium sensor that binds calcium through four EF-hand motifs and converts calcium binding into target regulation.

Regulates calcium channels and exchangers, including ryanodine receptors and NCKX4, to tune calcium release and calcium export.

Activates calmodulin-responsive kinases and phosphatases to propagate calcium-dependent signaling.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Comprehensive research report: Mus musculus Calm2 (UniProt P0DP27) / calmodulin-2

0) Target verification and scope control

1) Key concepts and definitions (current understanding)

1.1 Calmodulin (CaM) as a Ca2+ sensor

1.2 EF-hand motifs and Ca2+-dependent conformational switching

1.3 Bilobal functional partitioning (N-lobe vs C-lobe)

1.4 ApoCaM “pre-association” and target-binding motifs

2) Molecular function, pathways, and cellular localization of Calm2 product

2.1 Primary molecular function

2.2 Cellular localization

2.3 Major signaling pathways and targets (validated, mechanistic)

3) Recent developments and latest research (prioritize 2023–2024)

3.1 2023: Updated mechanistic synthesis of CaM regulation and calmodulinopathies

3.2 2023: Structural generalization of CaM–target binding modes

3.3 2024: Gene-specific therapeutic strategy leveraging CALM gene redundancy (real-world translational implementation)

4) Current applications and real-world implementations

4.1 Precision therapy concept for calmodulinopathies

4.2 Functional annotation-relevant use cases in physiology and disease modeling

5) Mouse-specific evidence for Calm2 (gene-level) and phenotype-relevant context

5.1 Calm2 expression dominance in mouse heart

5.2 Limitations: Calm2-specific mouse knockout/variant phenotype literature

6) Expert opinions and analysis from authoritative sources

7) Statistics and quantitative data (recent sources prioritized)

8) Visual evidence (figures)

9) Summary functional annotation (for Calm2 / CaM)

Key sources (with dates and URLs)

Citations

Notes

Calm2 notes

2026-03-19 ISO-focused review

Working curation rule

📄 View Raw YAML