Existing Annotations Review

GO Term	Evidence	Action	Reason
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
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:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization
GO:0005813 centrosome	IBA GO_REF:0000033	ACCEPT	Summary: Centrosomal localization for cell division Reason: Core calmodulin function or localization
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	ACCEPT	Summary: Cell cycle regulation at G2/M transition Reason: Core calmodulin function or localization
GO:0000922 spindle pole	IEA GO_REF:0000120	ACCEPT	Summary: Spindle pole localization during mitosis Reason: Core calmodulin function or localization
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:0005813 centrosome	IEA GO_REF:0000120	ACCEPT	Summary: Centrosomal localization for cell division Reason: Core calmodulin function or localization
GO:0005819 spindle	IEA GO_REF:0000044	ACCEPT	Summary: Spindle localization for cell division Reason: Core calmodulin function or localization
GO:0006897 endocytosis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Endocytosis regulation Reason: Tissue-specific or specialized function
GO:0031514 motile cilium	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Ciliary localization Reason: Tissue-specific or specialized function
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Parent term - too general Reason: Too general - more specific terms are available
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: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	ACCEPT	Summary: Heart rate regulation through ion channel modulation Reason: Core calmodulin function or localization
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: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	ACCEPT	Summary: Spindle microtubule association Reason: Core calmodulin function or localization
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	ACCEPT	Summary: Cardiac calcium-induced calcium release regulation Reason: Core calmodulin function or localization
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	KEEP AS NON CORE	Summary: IQ motif and calmodulin-binding domain recognition Reason: Tissue-specific or specialized function
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	ACCEPT	Summary: Regulates NOS enzymes Reason: Core calmodulin function or localization
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	ACCEPT	Summary: Cytokinesis regulation with CP110 and centrin Reason: Core calmodulin function or localization
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	ACCEPT	Summary: Binds NOS for activation Reason: Core calmodulin function or localization
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	ACCEPT	Summary: Cardiac contraction through calcium channel regulation Reason: Core calmodulin function or localization
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:0090150 establishment of protein localization to membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Membrane protein localization Reason: Tissue-specific or specialized function
GO:0090151 obsolete establishment of protein localization to mitochondrial membrane	IEA GO_REF:0000120	REMOVE	Summary: Term is obsolete - should be removed Reason: GO term is obsolete
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	KEEP AS NON CORE	Summary: Part of enzyme complexes Reason: Tissue-specific or specialized function
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:0000922 spindle pole	ISO GO_REF:0000119	ACCEPT	Summary: Spindle pole localization during mitosis Reason: Core calmodulin function or localization
GO:0002027 regulation of heart rate	ISO GO_REF:0000119	ACCEPT	Summary: Heart rate regulation through ion channel modulation Reason: Core calmodulin function or localization
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: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:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization
GO:0005813 centrosome	ISO GO_REF:0000119	ACCEPT	Summary: Centrosomal localization for cell division Reason: Core calmodulin function or localization
GO:0005829 cytosol	ISO GO_REF:0000119	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0005876 spindle microtubule	ISO GO_REF:0000119	ACCEPT	Summary: Spindle microtubule association 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	ACCEPT	Summary: Cardiac calcium-induced calcium release regulation Reason: Core calmodulin function or localization
GO:0016240 autophagosome membrane docking	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Autophagosome docking 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:0030017 sarcomere	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Sarcomere localization in muscle Reason: Tissue-specific or specialized function
GO:0031432 titin binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Titin binding in muscle Reason: Tissue-specific or specialized function
GO:0032465 regulation of cytokinesis	ISO GO_REF:0000119	ACCEPT	Summary: Cytokinesis regulation with CP110 and centrin Reason: Core calmodulin function or localization
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:0035458 cellular response to interferon-beta	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Interferon-beta response Reason: Tissue-specific or specialized function
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:0044325 transmembrane transporter binding	ISO GO_REF:0000119	ACCEPT	Summary: Binds ion channels and transporters Reason: Core calmodulin function or localization
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: JAK-STAT pathway regulation Reason: Tissue-specific or specialized function
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	ACCEPT	Summary: Cardiac contraction through calcium channel regulation Reason: Core calmodulin function or localization
GO:0060314 regulation of ryanodine-sensitive calcium-release channel activity	ISO GO_REF:0000119	ACCEPT	Summary: Regulates RyR1 and RyR2 activity Reason: Core calmodulin function or localization
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:0071346 cellular response to type II interferon	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Interferon-gamma response 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:0098901 regulation of cardiac muscle cell action potential	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Cardiac action potential regulation Reason: Tissue-specific or specialized function
GO:0140056 organelle localization by membrane tethering	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Organelle membrane tethering Reason: Tissue-specific or specialized function
GO:1901842 negative regulation of high voltage-gated calcium channel activity	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Calcium channel activity regulation Reason: Tissue-specific or specialized function
GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Cardiac electrical coupling regulation Reason: Tissue-specific or specialized function
GO:1902494 catalytic complex	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Part of enzyme complexes Reason: Tissue-specific or specialized function
GO:1990456 mitochondrion-endoplasmic reticulum membrane tethering	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ER-mitochondria contact regulation Reason: Tissue-specific or specialized function
GO:0000785 chromatin	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Chromatin association Reason: Tissue-specific or specialized function
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:0005634 nucleus	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Nuclear localization in some contexts Reason: Tissue-specific or specialized function
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: JAK-STAT signaling pathway Reason: Tissue-specific or specialized function
GO:0019904 protein domain specific binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: IQ motif and calmodulin-binding domain recognition Reason: Tissue-specific or specialized function
GO:0030235 nitric-oxide synthase regulator activity	ISO GO_REF:0000096	ACCEPT	Summary: Regulates NOS enzymes Reason: Core calmodulin function or localization
GO:0030426 growth cone	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Neuronal growth cone localization Reason: Tissue-specific or specialized function
GO:0030672 synaptic vesicle membrane	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Synaptic vesicle localization Reason: Tissue-specific or specialized function
GO:0031800 type 3 metabotropic glutamate receptor binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: mGluR3 binding in neurons Reason: Tissue-specific or specialized function
GO:0031966 mitochondrial membrane	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Mitochondrial membrane association Reason: Tissue-specific or specialized function
GO:0043209 myelin sheath	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Myelin sheath localization Reason: Tissue-specific or specialized function
GO:0043548 phosphatidylinositol 3-kinase binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: PI3K binding for signaling Reason: Tissue-specific or specialized function
GO:0044325 transmembrane transporter binding	ISO GO_REF:0000096	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	ACCEPT	Summary: Binds NOS for activation Reason: Core calmodulin function or localization
GO:0098685 Schaffer collateral - CA1 synapse	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Hippocampal synapse localization Reason: Tissue-specific or specialized function
GO:0099523 presynaptic cytosol	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Presynaptic localization Reason: Tissue-specific or specialized function
GO:0099524 postsynaptic cytosol	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Postsynaptic localization Reason: Tissue-specific or specialized function
GO:0005515 protein binding	IPI PMID:10620513 Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available Supporting Evidence: PMID:10620513 Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol trisphosphate receptors.
GO:0005515 protein binding	IPI PMID:11955285 Localization and function of a calmodulin-apocalmodulin-bind...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available Supporting Evidence: PMID:11955285 Localization and function of a calmodulin-apocalmodulin-binding domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor.
GO:0044305 calyx of Held	NAS PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Calyx of Held synapse localization Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0044305 calyx of Held	IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Calyx of Held synapse localization Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0044305 calyx of Held	IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Calyx of Held synapse localization Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0140238 presynaptic endocytosis	NAS PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Presynaptic vesicle endocytosis Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0140238 presynaptic endocytosis	IMP PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Presynaptic vesicle endocytosis Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0140238 presynaptic endocytosis	IDA PMID:31628181 Protein Kinase C and Calmodulin Serve As Calcium Sensors for...	KEEP AS NON CORE	Summary: Presynaptic vesicle endocytosis Reason: Tissue-specific or specialized function Supporting Evidence: PMID:31628181 Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
GO:0005515 protein binding	IPI PMID:29025071 The expression characteristics of FAM71D and its association...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available Supporting Evidence: PMID:29025071 The expression characteristics of FAM71D and its association with sperm motility.
GO:0097225 sperm midpiece	IDA PMID:29025071 The expression characteristics of FAM71D and its association...	KEEP AS NON CORE	Summary: Sperm midpiece localization Reason: Tissue-specific or specialized function Supporting Evidence: PMID:29025071 The expression characteristics of FAM71D and its association with sperm motility.
GO:0005515 protein binding	IPI PMID:31088288 The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc-...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available Supporting Evidence: PMID:31088288 Epub 2019 Jun 24. The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease.
GO:0016240 autophagosome membrane docking	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Autophagosome docking regulation Reason: Tissue-specific or specialized function
GO:0140056 organelle localization by membrane tethering	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Organelle membrane tethering Reason: Tissue-specific or specialized function
GO:1990456 mitochondrion-endoplasmic reticulum membrane tethering	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ER-mitochondria contact regulation Reason: Tissue-specific or specialized function
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 Oct 24. Structural analysis of the complex between calmodulin and full-length myelin basic protein, an intrinsically disordered molecule.
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9005848	KEEP AS NON CORE	Summary: Nucleoplasm localization Reason: Tissue-specific or specialized function
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9005872	KEEP AS NON CORE	Summary: Nucleoplasm localization Reason: Tissue-specific or specialized function
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9007015	KEEP AS NON CORE	Summary: Nucleoplasm localization Reason: Tissue-specific or specialized function
GO:0005829 cytosol	TAS Reactome:R-MMU-2025936	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0005829 cytosol	TAS Reactome:R-MMU-2316348	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0005829 cytosol	TAS Reactome:R-MMU-2316351	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
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:0060314 regulation of ryanodine-sensitive calcium-release channel activity	ISS GO_REF:0000024	ACCEPT	Summary: Regulates RyR1 and RyR2 activity 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 ...	ACCEPT	Summary: Cell cycle regulation at G2/M transition Reason: Core calmodulin function or localization 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. file:mouse/Calm1/Calm1-deep-research-falcon.md Deep research synthesis supports Calm1 as a canonical four-EF-hand calcium sensor with gene-specific regulation dominated by transcript-level control rather than a distinct protein sequence.

Core Functions

Primary calcium-sensing protein that binds calcium ions through four EF-hand domains, undergoing conformational changes that enable interaction with over 100 target proteins.

Molecular Function:

calcium ion binding

Directly Involved In:

detection of calcium ion

Cellular Locations:

cytosol

Supporting Evidence:

UniProtKB:P0DP26
Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding

Regulates calcium-dependent protein kinases (CaMKII, CaMKIV) and phosphatases (calcineurin/PP2B) for signal transduction.

Molecular Function:

protein serine/threonine kinase activator activity

Directly Involved In:

calcineurin-mediated signaling

Cellular Locations:

cytosol

Supporting Evidence:

UniProtKB:P0DP26
Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases

Regulates ryanodine receptors (RyR1, RyR2) and IP3 receptors for calcium release from intracellular stores, essential for cardiac and skeletal muscle function.

Molecular Function:

calcium channel regulator activity

Directly Involved In:

regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum

Cellular Locations:

cytosol

Supporting Evidence:

PMID:10620513
Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol trisphosphate receptors

Localizes to centrosomes and spindle during mitosis, regulating cytokinesis through interaction with CP110 and centrin.

Molecular Function:

protein kinase binding

Directly Involved In:

regulation of cytokinesis G2/M transition of mitotic cell cycle

Cellular Locations:

centrosome spindle pole

Supporting Evidence:

UniProtKB:P0DP26
Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis

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:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

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:10620513

Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol trisphosphate receptors.

PMID:11955285

Localization and function of a calmodulin-apocalmodulin-binding domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor.

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:29025071

The expression characteristics of FAM71D and its association with sperm motility.

PMID:31088288

The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease.

PMID:31628181

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

file:mouse/Calm1/Calm1-deep-research-falcon.md

Falcon deep research summary for mouse Calm1

Reactome:R-MMU-2025936

Calcineurin Dephosphorylates Nfatc2

Reactome:R-MMU-2316348

RalA:GTP binds Myo1c:Calm1 and F-actin

Reactome:R-MMU-2316351

Translocation of Glut4 Vesicle and Docking at the Plasma Membrane

Reactome:R-MMU-9005848

Active Prkaca and CaMK IV phosphorylate Mecp2 at T308

Reactome:R-MMU-9005872

Active Prkaca, CAMK IV does not phosphorylate Mecp2_e2 mutant R306C at T308

Reactome:R-MMU-9007015

Mecp2 is phosphorylated at S421

📚 Additional Documentation

Deep Research Bioreason

(Calm1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:32 AM

Organism: Mus musculus

Sequence:

MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTAK

Thinking Trace

I begin with the InterPro architecture. The sequence is dominated by calcium-sensor modules: IPR011992 (EF-hand domain pair, homologous_superfamily, residues 2–147) frames the core as a paired EF-hand scaffold typical of calcium-switch proteins. This is reinforced by IPR002048 (EF-hand domain, residues 8–149), indicating multiple helix–loop–helix calcium-binding motifs arrayed across most of the polypeptide. IPR018247 (EF-Hand 1, calcium-binding site, residues 21–142) specifies conserved Ca2+-coordinating loops distributed through the interior of the protein, implying multiple functional Ca2+ sites rather than a single regulatory site. The overall fold and lineage are cemented by IPR050230 (Calmodulin/Myosin light chain/Troponin C-like family, residues 2–148), which places the protein within the canonical Ca2+-sensor family that toggles between apo and Ca2+-bound conformations to regulate target enzymes and cytoskeletal assemblies. The ordered architecture—an EF-hand pair spanning nearly the entire length within a calmodulin-like family—causes Ca2+-dependent conformational changes that expose or occlude hydrophobic pockets for target binding.

From this architecture, the molecular function resolves as calcium ion binding. The repeated EF-hand motifs and their paired arrangement (IPR011992 and IPR002048) create high-affinity Ca2+-binding sites that stabilize specific tertiary states, and IPR018247 marks the precise Ca2+-coordinating loops that drive this switch. This directly supports GO:0005509 calcium ion binding as the primary molecular function.

A calmodulin-like Ca2+ sensor typically transduces Ca2+ fluctuations into control of downstream pathways. The EF-hand-driven conformational toggling allows the protein to regulate enzymes and structural assemblies that execute Ca2+ signaling. This causal link from Ca2+ sensing to pathway control situates the protein within calcium-mediated signaling, captured by GO:0019722 calcium-mediated signaling. Through this signaling axis, the protein can modulate diverse outputs—energy metabolism, contractility, and transcription—depending on its Ca2+-bound state and target repertoire.

Cellular location follows from the soluble EF-hand scaffold and the absence of transmembrane features in the domain composition. Calmodulin-like sensors operate as soluble regulators that shuttle between cytoplasmic and nuclear compartments to engage targets and transcriptional machinery. Thus, the architecture predicts a soluble distribution centered in the cytoplasm (GO:0005737) with functional excursions into the nucleus (GO:0005634), consistent with Ca2+-regulated control of cytosolic enzymes and nuclear effectors.

Mechanistically, Ca2+ binding across multiple EF-hands induces an open conformation that clamps onto amphipathic target helices (e.g., IQ or 1-8-14 motifs). This switching likely governs interactions with Ca2+-sensitive enzymes and assemblies. I hypothesize that physiological partners include Ca2+/calmodulin-dependent kinases and phosphatases, myosin light-chain–like targets, and transcriptional regulators whose activity or localization is tuned by Ca2+. Such interactions would allow the protein to couple transient Ca2+ spikes to enzyme activation, cytoskeletal dynamics, and gene regulatory programs within cytoplasmic and nuclear spaces.

Functional Summary

A soluble calcium-sensing regulator in mouse that uses multiple EF-hand motifs to bind Ca2+ and undergo conformational switching, thereby engaging diverse target proteins to transmit calcium signals. By toggling between Ca2+-bound and apo states, it modulates enzyme and cytoskeletal activities and influences nuclear programs. Its soluble architecture supports operation in the cytoplasm with functional access to the nucleus, where calcium-triggered binding events orchestrate downstream signaling pathways.

UniProt Summary

Calmodulin-like calcium-binding protein.

InterPro Domains

EF-hand domain pair (IPR011992, homologous_superfamily) — residues 2-147
Calmodulin/Myosin light chain/Troponin C-like (IPR050230, family) — residues 2-148
EF-hand domain (IPR002048, domain) — residues 8-149
EF-Hand 1, calcium-binding site (IPR018247, binding_site) — residues 21-142

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), ion binding (GO:0043167), cation binding (GO:0043169), metal ion binding (GO:0046872), calcium ion binding (GO:0005509)

Biological Process: biological_process (GO:0008150), cellular process (GO:0009987), biological regulation (GO:0065007), regulation of molecular function (GO:0065009), cell cycle process (GO:0022402), cell cycle (GO:0007049), mitotic cell cycle process (GO:1903047), mitotic cell cycle (GO:0000278), cell cycle phase transition (GO:0044770), positive regulation of molecular function (GO:0044093), regulation of binding (GO:0051098), positive regulation of binding (GO:0051099), regulation of DNA binding (GO:0051101), cell cycle G2/M phase transition (GO:0044839), mitotic cell cycle phase transition (GO:0044772), positive regulation of DNA binding (GO:0043388), G2/M transition of mitotic cell cycle (GO:0000086)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), organelle (GO:0043226), membrane (GO:0016020), cell periphery (GO:0071944), membrane protein complex (GO:0098796), myelin sheath (GO:0043209), transporter complex (GO:1990351), plasma membrane protein complex (GO:0098797), transmembrane transporter complex (GO:1902495), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), ion channel complex (GO:0034702), vesicle (GO:0031982), voltage-gated potassium channel complex (GO:0008076), cation channel complex (GO:0034703), potassium channel complex (GO:0034705)

Generated by BioReason

Deep Research Bioreason Rl

(Calm1-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:32 AM

Organism: Mus musculus

Sequence:

MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTAK

Thinking Trace

Functional Summary

UniProt Summary

Calmodulin-like calcium-binding protein.

InterPro Domains

EF-hand domain pair (IPR011992, homologous_superfamily) — residues 2-147
Calmodulin/Myosin light chain/Troponin C-like (IPR050230, family) — residues 2-148
EF-hand domain (IPR002048, domain) — residues 8-149
EF-Hand 1, calcium-binding site (IPR018247, binding_site) — residues 21-142

GO Terms

Generated by BioReason

Deep Research Falcon

(Calm1-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
template_variables:
organism: mouse
gene_id: Calm1
gene_symbol: Calm1
uniprot_accession: P0DP26
protein_description: 'RecName: Full=Calmodulin-1 {ECO:0000250|UniProtKB:P0DP23};'
gene_info: Name=Calm1 {ECO:0000312|MGI:MGI:88251}; Synonyms=Calm, Cam, Cam1;
organism_full: Mus musculus (Mouse).
protein_family: Belongs to the calmodulin family. .
protein_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)
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citation_count: 40

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: P0DP26
Protein Description: RecName: Full=Calmodulin-1 {ECO:0000250|UniProtKB:P0DP23};
Gene Information: Name=Calm1 {ECO:0000312|MGI:MGI:88251}; Synonyms=Calm, Cam, Cam1;
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 "Calm1" 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 'Calm1' 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 Calm1 (gene ID: Calm1, UniProt: P0DP26) 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: P0DP26
Protein Description: RecName: Full=Calmodulin-1 {ECO:0000250|UniProtKB:P0DP23};
Gene Information: Name=Calm1 {ECO:0000312|MGI:MGI:88251}; Synonyms=Calm, Cam, Cam1;
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 "Calm1" 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 Calm1 (gene ID: Calm1, UniProt: P0DP26) 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.

Research Report: Mouse Calm1 (UniProt P0DP26) / Calmodulin-1

Scope and identity verification (MANDATORY)

The requested target is Mus musculus Calm1, encoding calmodulin-1 (CaM), a ubiquitous Ca2+ sensor protein of 149 amino acids. In mammals there are three distinct genes (Calm1, Calm2, Calm3) that encode an identical calmodulin protein sequence; their functional differences are primarily mediated through gene-specific regulatory elements, especially distinct 5′/3′ UTRs and expression programs rather than distinct protein chemistry. This identity and the distinction from other CALM genes are explicitly supported by mouse genetic and regulatory studies focused on Calm1 and by a 2024 authoritative review of calmodulin structure and function. (bae2020eliminationofcalm1 pages 1-2, tsai2025enrichmentofmutant pages 1-6, sobue2024calmodulinahighly pages 1-2)

1) Key concepts and definitions (current understanding)

Calmodulin (CaM) as a Ca2+ “sensor/transducer”

Calmodulin is best defined as a non-enzymatic Ca2+-binding effector that converts changes in free intracellular Ca2+ into regulated binding and activity changes in diverse target proteins (kinases, phosphatases, ion channels, pumps, cytoskeletal regulators). Rather than catalyzing a chemical reaction, CaM primarily functions through Ca2+-dependent conformational switching and target engagement. (sobue2024calmodulinahighly pages 2-4, sobue2024calmodulinahighly pages 1-2)

EF-hand structure and Ca2+-binding sites

A central structural concept is that CaM has a dumbbell-like architecture, with N- and C-terminal globular lobes connected by a central α-helix. Each lobe contains two EF-hand helix–loop–helix motifs, yielding four EF-hand Ca2+-binding sites per CaM molecule. (sobue2024calmodulinahighly pages 1-2)

Physiological Ca2+ regime CaM is tuned for

A 2024 review summarizes canonical Ca2+ gradients and signaling ranges: resting free cytosolic Ca2+ is ~10−7 M, extracellular Ca2+ is ~10−3 M, and cellular stimulation can raise intracellular Ca2+ into the 10−6–10−5 M range where CaM-dependent processes become engaged. CaM abundance is reported at ~2–10 μM in mammalian cells, enabling it to act as a highly available Ca2+ decoder. (sobue2024calmodulinahighly pages 1-2)

2) Recent developments and latest research (prioritizing 2023–2024)

2024: Consolidated modern view of CaM as a “master Ca2+ decoder”

A 2024 review emphasizes CaM’s high conservation, ubiquitous expression, and broad target repertoire, highlighting that Ca2+ saturation drives a conformational change in which CaM becomes more elongated and exposes hydrophobic surfaces that support binding to diverse targets. It also synthesizes how CaM participates in neuronal (e.g., CaMKII, calcineurin/NFAT), cardiac (RyR regulation, Ca2+ handling), and cytoskeletal signaling modules. (Sobue, 2024-07, https://doi.org/10.2183/pjab.100.025) (sobue2024calmodulinahighly pages 2-4, sobue2024calmodulinahighly pages 1-2)

2023: CaM-dependent CaMKII as an actionable therapeutic axis

A high-authority 2023 Annual Review frames CaMKII as a multifunctional Ca2+/calmodulin-dependent kinase central to cardiovascular disease mechanisms. While this review is not “Calm1-specific” at the gene level, it is directly relevant to Calm1 protein function because the calmodulin sequence encoded by Calm1 is identical to that encoded by Calm2/3. The review underscores CaM binding as the initiating event that releases CaMKII autoinhibition and enables phosphorylation of downstream targets involved in excitation–contraction coupling and remodeling (e.g., LTCC, RyR2, PLN, SERCA2, transcriptional regulators). (Gaido et al., 2023-01, https://doi.org/10.1146/annurev-pharmtox-051421-111814) (gaido2023camkiiasa pages 25-28)

A 2023 review of CaMKII provides a mechanistic description of how Ca2+/CaM binding to CaMKII’s regulatory region disrupts autoinhibition, with Thr286 autophosphorylation providing an additional route to sustained activity and signal integration. This clarifies the fundamental “molecular switch” logic that underpins a major fraction of CaM biology in excitable tissues. (Rostas & Skelding, 2023-01, https://doi.org/10.3390/cells12030401) (rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2)

2023: CaM requirement in calcineurin/CaMKII control of an ion channel (example: Cav3.2)

A 2023 primary study on Cav3.2 regulation experimentally demonstrates CaM as an enabling cofactor in both calcineurin- and CaMKII-dependent biochemical reactions on an ion channel substrate, by including recombinant calmodulin in in vitro dephosphorylation/phosphorylation assays. This provides a clear, target-level illustration of CaM acting as a shared dependency connecting Ca2+ signals to both phosphatase and kinase arms of regulation. (Chang et al., 2023-10, https://doi.org/10.3390/biomedicines11112891) (chang2023identificationofnovel pages 2-4)

3) Primary function, biological processes, and major pathways

Primary molecular function

Calm1 encodes calmodulin, whose primary function is high-affinity, cooperative Ca2+ binding via EF-hands, and Ca2+-dependent binding/regulation of target proteins. Ca2+ binding drives a conformational transition (elongation and exposure of hydrophobic residues) that enables target recognition and functional regulation. (sobue2024calmodulinahighly pages 2-4, sobue2024calmodulinahighly pages 1-2)

Major downstream pathways and target classes

1) CaMKII signaling (neuronal and cardiovascular)
CaMKII is activated when Ca2+/CaM binds its regulatory region and releases autoinhibition, enabling phosphorylation of downstream substrates; autophosphorylation further stabilizes activity states that can persist after Ca2+ declines. (rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2, gaido2023camkiiasa pages 25-28)

2) Calcineurin/NFAT signaling
Calcineurin is a Ca2+/calmodulin-dependent phosphatase. A 2023 review describes a mechanistic activation sequence: Ca2+ binding to the calcineurin regulatory subunit triggers conformational changes that permit calmodulin binding and displacement of the autoinhibitory domain, enabling phosphatase activity. Active calcineurin then dephosphorylates NFAT, exposing an NLS and promoting NFAT nuclear import and transcriptional responses. (Nolze et al., 2023-09, https://doi.org/10.3390/cells12182269) (nolze2023calcineurinisa pages 1-3)

3) Ryanodine receptor (RyR) regulation and Ca2+ release channel control
A 2024 review summarizes classic functional distinctions between Ca2+-free and Ca2+-bound calmodulin in RyR regulation (apoCaM at low Ca2+ vs Ca2+/CaM at higher Ca2+), reflecting CaM’s role as a bidirectional modulator of Ca2+ release channels and excitation–contraction coupling. (sobue2024calmodulinahighly pages 2-4)

4) Mouse Calm1-specific regulation, localization, and phenotypes

A key point for functional annotation is that Calm1-specific biology in mouse is strongly supported at the transcript-regulatory level.

Alternative polyadenylation (APA) creates two Calm1 3′-UTR isoforms

Mouse Calm1 produces at least two major mRNA isoforms via APA:
- Calm1-S: short ~0.9 kb 3′ UTR
- Calm1-L: long ~3.4 kb 3′ UTR
These isoforms encode the same calmodulin protein but are associated with distinct tissue enrichment, subcellular localization, and stability. (Gruner et al., 2019-02, https://doi.org/10.1101/553990; Bae et al., 2020-06, https://doi.org/10.1261/rna.076430.120) (gruner2019preciseremovalof pages 4-8, bae2020eliminationofcalm1 pages 2-4)

Tissue enrichment of Calm1-L in neural tissues

Northern-based quantification reported a strong neural enrichment of Calm1-L: the cortex long/short (L/S) ratio was 11.8-fold greater than liver. (gruner2019preciseremovalof pages 4-8)

Subcellular localization differences in DRG neurons

In dorsal root ganglion neurons, isoform-specific in situ/FISH evidence supports compartmentalization:
- Signals detecting all Calm1 isoforms extend into axons.
- The long-UTR-specific signal (Calm1-L) is largely somatic and shows little to no axonal signal.
This implies Calm1-S is relatively more axon-associated in DRG neurons. (gruner2019preciseremovalof pages 4-8, bae2020eliminationofcalm1 pages 2-4)

RNA stability differences

Calm1-S is more stable than Calm1-L in decay experiments:
- Calm1-S t1/2 = 5.9 ± 1.4 h
- Calm1-L t1/2 = 2.6 ± 0.6 h
(Bae et al., 2020-06, https://doi.org/10.1261/rna.076430.120) (bae2020eliminationofcalm1 pages 10-11)

In vivo phenotypes from isoform-specific perturbation

CRISPR removal of the distal poly(A) site selectively eliminated Calm1-L while preserving Calm1-S expression. In these mice, major phenotypes were reported despite unchanged overall CaM protein levels:
- Embryonic DRG developmental defects (disorganized axon and cell body migration; increased fasciculation in explants).
- Reduced experience-induced hippocampal neuronal activation, quantified by CA1 cFos induction after enriched environment: 31.9 ± 12.5% (WT) vs 19.8 ± 9.1% (Calm1ΔL/ΔL). (gruner2019preciseremovalof pages 4-8, bae2020eliminationofcalm1 pages 8-10)

These findings support a functional annotation where Calm1’s gene-specific contribution is mediated through neural-tissue APA regulation and mRNA localization/stability, enabling specialized neuronal development and activity-dependent responses even though the encoded protein is shared with Calm2/3. (bae2020eliminationofcalm1 pages 1-2, bae2020eliminationofcalm1 pages 2-4)

5) Current applications and real-world implementations

CaM as an engineered module in GCaMP-type genetically encoded Ca2+ indicators (GECIs)

A dominant real-world implementation of calmodulin biology is its use as the Ca2+ sensing module in widely deployed fluorescent biosensors. GCaMP-family sensors are engineered fusions of calmodulin (CaM), a CaM-binding peptide, and circularly permuted GFP, where Ca2+-dependent CaM–peptide interactions modulate fluorescence. (latifi2024windowintothe pages 3-4)

2023 Nature: jGCaMP8 enables millisecond-timescale population imaging

Zhang et al. (Nature, 2023-11, https://doi.org/10.1038/s41586-023-05828-9) reported the jGCaMP8 series, a CaM-based sensor family engineered through screening and structure-guided mutagenesis. Key performance statistics include:
- Half-rise time ~2 ms
- Resolves spiking up to 50 Hz
These improvements address a long-standing tradeoff between sensitivity and kinetics in population Ca2+ imaging. (zhang2023fastandsensitive pages 1-2)

The jGCaMP8 modular design (CaM + CaM-binding peptide + cpGFP and engineered linkers) is shown in the retrieved figure crop. (zhang2023fastandsensitive media 0c163603)

2024 engineering: ultrahigh-affinity CaM-based indicators

Hara et al. (Communications Biology, 2024-06, https://doi.org/10.1038/s42003-024-06394-0) report CaM-based 1FP-type indicators with ultrahigh Ca2+ affinity:
- Kd = 17–25 nM
This enables detection of low-nanomolar Ca2+ regimes that are otherwise challenging for typical indicators. (hara2024highaffinitytuningof pages 1-2)

6) Expert opinion and analysis (authoritative synthesis)

The 2024 calmodulin review positions CaM as a conserved and ubiquitous Ca2+ sensor whose functional breadth arises from its ability to couple a relatively narrow biophysical input (Ca2+ binding over physiological ranges) to an extremely broad spectrum of targets, including kinases (e.g., CaMKII), phosphatases (calcineurin), and channels (e.g., RyR). This “master decoder” framing is consistent with the observation that mammals retained multiple genes encoding an identical CaM protein, suggesting evolutionary value in regulatory diversity rather than protein diversification. (sobue2024calmodulinahighly pages 2-4, bae2020eliminationofcalm1 pages 1-2)

For mouse Calm1 specifically, the most compelling gene-level expert inference from the available evidence is: Calm1’s distinctive biological role is likely driven by mRNA-level regulation (APA-dependent UTRs, stability, and neuronal localization), enabling precise spatiotemporal control of CaM protein availability near Ca2+ microdomains and local translation sites, particularly in neurons. This inference is directly supported by isoform-specific knockout phenotypes in DRG development and hippocampal activity measures. (gruner2019preciseremovalof pages 4-8, bae2020eliminationofcalm1 pages 8-10)

7) Relevant statistics and recent data highlights (selected)

CaM protein: 149 aa, 4 EF-hand Ca2+ binding sites, cellular abundance ~2–10 μM. (sobue2024calmodulinahighly pages 1-2)
Ca2+ regimes: cytosol resting ~10−7 M, stimulated ~10−6–10−5 M, extracellular ~10−3 M. (sobue2024calmodulinahighly pages 1-2)
Calm1 transcripts: 0.9 kb (short 3′ UTR) vs 3.4 kb (long 3′ UTR); cortex:liver L/S 11.8×. (gruner2019preciseremovalof pages 4-8)
RNA stability: Calm1-S t1/2 5.9 ± 1.4 h vs Calm1-L t1/2 2.6 ± 0.6 h. (bae2020eliminationofcalm1 pages 10-11)
Adult hippocampal activity: CA1 enriched-environment cFos 31.9 ± 12.5% (WT) vs 19.8 ± 9.1% (Calm1ΔL/ΔL). (bae2020eliminationofcalm1 pages 8-10)
jGCaMP8 (Nature 2023): half-rise ~2 ms, spikes resolvable up to 50 Hz. (zhang2023fastandsensitive pages 1-2)
Ultrafine-affinity CaM-based indicators (2024): Kd 17–25 nM. (hara2024highaffinitytuningof pages 1-2)

Summary table (evidence map)

Topic	Key points	Key quantitative values	Best supporting citations
Identity / structure	• Verified target is mouse Calm1 / calmodulin-1 (UniProt P0DP26), not a different similarly named gene. • Mammals have three CALM genes (Calm1/2/3) that encode an identical calmodulin protein; paralog differences are mainly in UTRs/regulation. • CaM is a ~150 aa, dumbbell-shaped Ca2+ sensor with N- and C-terminal lobes linked by a central helix. • Each lobe contains two EF-hand helix-loop-helix Ca2+-binding motifs.	• 149 aa protein • 4 EF-hands / 4 Ca2+-binding sites • Cellular CaM abundance in mammals: ~2–10 µM	(bae2020eliminationofcalm1 pages 1-2, tsai2025enrichmentofmutant pages 1-6, sobue2024calmodulinahighly pages 1-2)
Core molecular function	• CaM is the principal intracellular Ca2+ sensor/transducer rather than an enzyme or transporter. • Binding Ca2+ triggers a conformational change that elongates CaM and exposes hydrophobic surfaces for target binding. • CaM decodes Ca2+ spikes and couples them to enzymes, channels, pumps, and cytoskeletal regulators.	• Resting cytosolic Ca2+: ~10^-7 M • Extracellular Ca2+: ~10^-3 M • Stimulated intracellular Ca2+: ~10^-6 to 10^-5 M • Reported CaM Ca2+ affinity range: Kd ~5×10^-7 to 5×10^-6 M	(sobue2024calmodulinahighly pages 2-4, sobue2024calmodulinahighly pages 1-2)
Major pathways / targets	• CaMKII: Ca2+/CaM binding relieves autoinhibition and enables substrate phosphorylation; Thr286 autophosphorylation can sustain autonomous activity. • Calcineurin/NFAT: calcineurin is activated by Ca2+/CaM, then dephosphorylates NFAT to promote nuclear import/transcription. • Ion channels: CaM regulates RyR, LTCC, SK/IK channels, Cav3.2, and other excitability proteins. • In heart, CaM-dependent CaMKII signaling affects RyR2, PLN, SERCA2, LTCC, NFAT-linked remodeling.	• CaMKII is ~1–2% of forebrain protein • RyR responses differ for apoCaM <5×10^-7 M Ca2+ vs Ca2+/CaM >10^-6 M • Calcineurin regulatory subunit contains 4 EF-hands	(sobue2024calmodulinahighly pages 2-4, gaido2023camkiiasa pages 20-21, gaido2023camkiiasa pages 25-28, rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2, chang2023identificationofnovel pages 2-4, nolze2023calcineurinisa pages 1-3)
Mouse-specific regulation	• Calm1 has strong post-transcriptional regulation via alternative polyadenylation. • It produces Calm1-S and Calm1-L transcripts with identical coding sequence but distinct 3′ UTRs. • Calm1-L is neuron-enriched, especially in cortex/hippocampus/DRG; Calm1-S is broader and more axon-enriched. • Calm1-L is less stable than Calm1-S.	• 3′ UTR lengths: Calm1-S ~0.9 kb, Calm1-L ~3.4 kb • Cortex:liver long/short enrichment: 11.8-fold • Long isoform fraction: ~0.46 in cortex vs 0.12–0.28 in non-brain tissues • Half-life: Calm1-S 5.9 ± 1.4 h, Calm1-L 2.6 ± 0.6 h	(gruner2019preciseremovalof pages 4-8, gruner2019preciseremovalof pages 35-37, bae2020eliminationofcalm1 pages 10-11, bae2020eliminationofcalm1 pages 2-4)
Localization	• CaM protein is broadly intracellular; functionally enriched where Ca2+ signals occur, including cytosol, membrane-associated channel complexes, and neuronal/synaptic compartments. • In mouse DRG neurons, Calm1-L is mainly somatic, while Calm1-S/all-isoform signal extends into axons. • In hippocampal neurons, both isoforms can localize to neural processes, but DRG shows clearer compartment bias. • In mutant mouse heart, CALM showed a striated pattern compatible with Z-line enrichment.	• QAPA long-isoform fraction: ~23% in whole DRG vs ~11% in isolated axons • FISH neuron enrichment: P ≤ 0.0001 for ext/uni differences in Tubb3+ cells	(gruner2019preciseremovalof pages 26-29, bae2020eliminationofcalm1 pages 2-4, bae2020eliminationofcalm1 pages 8-10, tsai2025enrichmentofmutant pages 6-10)
Genetics / phenotypes	• Isoform-specific CRISPR deletion of Calm1-L preserves total CaM protein yet causes developmental and neuronal activity phenotypes, supporting transcript-level specialization. • Calm1-L loss causes disorganized DRG migration/axon patterning and increased fasciculation in explants. • In adult hippocampus, Calm1-L loss reduces experience-induced neuronal activation. • Redox-sensitive Calm1 mutations can alter growth, behavior, myogenesis, and target activation.	• Calm1-L CRISPR deletion removed ~164 bp around distal poly(A) site • EE-induced cFos in CA1: 31.9 ± 12.5% WT vs 19.8 ± 9.1% Calm1ΔL/ΔL • M77Q mice were ~20% smaller and ran ~20% longer in treadmill testing	(gruner2019preciseremovalof pages 1-4, bae2020eliminationofcalm1 pages 10-11, bae2020eliminationofcalm1 pages 8-10, steil2020thecalmodulinredox pages 1-2)
2023–2024 developments	• 2024 review literature emphasizes CaM as a highly conserved, ubiquitous master Ca2+ decoder integrating channels, kinases, phosphatases, and cytoskeleton. • 2023–2024 pathway reviews sharpen mechanistic framing of CaMKII and calcineurin as key CaM effectors in cardiovascular and neural contexts. • Recent work highlights pathway- and microenvironment-specific consequences of CaM-dependent CaMKII activation.	• 2024 CaM review in Proc. Jpn. Acad. B • 2023 CaMKII cardiovascular review in Annu Rev Pharmacol Toxicol • 2023 CaMKII microenvironment review in Cells	(sobue2024calmodulinahighly pages 2-4, gaido2023camkiiasa pages 20-21, rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2, nolze2023calcineurinisa pages 1-3)
Applications / tools	• CaM is a core module in GCaMP/jGCaMP and related genetically encoded calcium indicators (GECIs). • GCaMP architecture couples CaM + CaM-binding peptide + cpGFP to optical readout of Ca2+. • These tools are widely implemented in two-photon imaging, fiber photometry, organoids, and circuit mapping. • New engineering efforts tune kinetics, affinity, color, and fluorescence lifetime.	• jGCaMP8 half-rise time: ~2 ms • jGCaMP8 can resolve spikes up to ~50 Hz • Typical fluorescence increases for some GECIs: ~3–10-fold • Ultrafine-affinity engineered GECIs: Kd 17–25 nM	(zhang2023fastandsensitive pages 1-2, latifi2024windowintothe pages 3-4, hara2024highaffinitytuningof pages 1-2, gonzalezramos2024updatedtoolboxfor pages 6-7, zhang2023fastandsensitive media 0c163603)
Quantitative highlights	• Calm1/2/3 encode the same protein, so gene-specific biology is largely regulatory rather than coding-sequence driven. • Mouse Calm1 evidence is strongest for neuron-specific transcript regulation, not a unique protein chemistry versus Calm2/3. • Quantitative metrics support both canonical CaM biophysics and Calm1-specific transcript specialization.	• Protein length 149 aa • 4 EF-hands • CaM abundance 2–10 µM • Ca2+ activation window 10^-7 to 10^-5 M • Calm1-L/S UTRs 3.4 kb / 0.9 kb • Cortex:liver L/S 11.8 • Half-lives 5.9 h vs 2.6 h • cFos 31.9% vs 19.8% • jGCaMP8 rise 2 ms • Nano-GECI Kd 17–25 nM	(sobue2024calmodulinahighly pages 1-2, gruner2019preciseremovalof pages 4-8, bae2020eliminationofcalm1 pages 10-11, bae2020eliminationofcalm1 pages 8-10, zhang2023fastandsensitive pages 1-2, hara2024highaffinitytuningof pages 1-2)

Table: This table condenses the main evidence for mouse Calm1/calmodulin-1, covering identity, molecular function, regulation, localization, phenotypes, and recent tool/applications. It is designed to support a comprehensive research report with quick access to quantitative values and supporting context IDs.

Retrieved figure (visual evidence)

The jGCaMP8 CaM-based indicator architecture (cpGFP + CaM + CaM-binding peptide with engineered linkers/mutations) is shown in a cropped figure from the 2023 Nature paper. (zhang2023fastandsensitive media 0c163603)

References

(bae2020eliminationofcalm1 pages 1-2): Bongmin Bae, Hannah N. Gruner, Maebh Lynch, Ting Feng, Kevin So, Daniel Oliver, Grant S. Mastick, Wei Yan, Simon Pieraut, and Pedro Miura. Elimination of calm1 long 3′-utr mrna isoform by crispr–cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice. RNA, 26:1414-1430, Jun 2020. URL: https://doi.org/10.1261/rna.076430.120, doi:10.1261/rna.076430.120. This article has 46 citations and is from a domain leading peer-reviewed journal.
(tsai2025enrichmentofmutant pages 1-6): 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 0 citations and is from a domain leading peer-reviewed journal.
(sobue2024calmodulinahighly pages 1-2): Kenji Sobue. Calmodulin: a highly conserved and ubiquitous ca2+ sensor. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 100:368-386, Jul 2024. URL: https://doi.org/10.2183/pjab.100.025, doi:10.2183/pjab.100.025. This article has 5 citations.
(sobue2024calmodulinahighly pages 2-4): Kenji Sobue. Calmodulin: a highly conserved and ubiquitous ca2+ sensor. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 100:368-386, Jul 2024. URL: https://doi.org/10.2183/pjab.100.025, doi:10.2183/pjab.100.025. This article has 5 citations.
(gaido2023camkiiasa pages 25-28): Oscar E. Reyes Gaido, Lubika J. Nkashama, Kate L. Schole, Qinchuan Wang, Priya Umapathi, Olurotimi O. Mesubi, Klitos Konstantinidis, Elizabeth D. Luczak, and Mark E. Anderson. Camkii as a therapeutic target in cardiovascular disease. Annual Review of Pharmacology and Toxicology, 63:249-272, Jan 2023. URL: https://doi.org/10.1146/annurev-pharmtox-051421-111814, doi:10.1146/annurev-pharmtox-051421-111814. This article has 122 citations and is from a highest quality peer-reviewed journal.
(rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2): John A. P. Rostas and Kathryn A. Skelding. Calcium/calmodulin-stimulated protein kinase ii (camkii): different functional outcomes from activation, depending on the cellular microenvironment. Cells, 12:401, Jan 2023. URL: https://doi.org/10.3390/cells12030401, doi:10.3390/cells12030401. This article has 84 citations.
(chang2023identificationofnovel pages 2-4): Yu-Wang Chang, Yong-Cyuan Chen, and Chien-Chang Chen. Identification of novel targeting sites of calcineurin and camkii in human cav3.2 t-type calcium channel. Biomedicines, 11:2891, Oct 2023. URL: https://doi.org/10.3390/biomedicines11112891, doi:10.3390/biomedicines11112891. This article has 2 citations.
(nolze2023calcineurinisa pages 1-3): Alexander Nolze, Sebastian Matern, and Claudia Grossmann. Calcineurin is a universal regulator of vessel function—focus on vascular smooth muscle cells. Cells, 12:2269, Sep 2023. URL: https://doi.org/10.3390/cells12182269, doi:10.3390/cells12182269. This article has 14 citations.
(gruner2019preciseremovalof pages 4-8): Hannah N. Gruner, Bongmin Bae, Maebh Lynch, Daniel Oliver, Kevin So, Grant S. Mastick, Wei Yan, and Pedro Miura. Precise removal of calm1 long 3′ utr isoform by crispr-cas9 genome editing impairs dorsal root ganglion development in mice. bioRxiv, Feb 2019. URL: https://doi.org/10.1101/553990, doi:10.1101/553990. This article has 3 citations.
(bae2020eliminationofcalm1 pages 2-4): Bongmin Bae, Hannah N. Gruner, Maebh Lynch, Ting Feng, Kevin So, Daniel Oliver, Grant S. Mastick, Wei Yan, Simon Pieraut, and Pedro Miura. Elimination of calm1 long 3′-utr mrna isoform by crispr–cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice. RNA, 26:1414-1430, Jun 2020. URL: https://doi.org/10.1261/rna.076430.120, doi:10.1261/rna.076430.120. This article has 46 citations and is from a domain leading peer-reviewed journal.
(bae2020eliminationofcalm1 pages 10-11): Bongmin Bae, Hannah N. Gruner, Maebh Lynch, Ting Feng, Kevin So, Daniel Oliver, Grant S. Mastick, Wei Yan, Simon Pieraut, and Pedro Miura. Elimination of calm1 long 3′-utr mrna isoform by crispr–cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice. RNA, 26:1414-1430, Jun 2020. URL: https://doi.org/10.1261/rna.076430.120, doi:10.1261/rna.076430.120. This article has 46 citations and is from a domain leading peer-reviewed journal.
(bae2020eliminationofcalm1 pages 8-10): Bongmin Bae, Hannah N. Gruner, Maebh Lynch, Ting Feng, Kevin So, Daniel Oliver, Grant S. Mastick, Wei Yan, Simon Pieraut, and Pedro Miura. Elimination of calm1 long 3′-utr mrna isoform by crispr–cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice. RNA, 26:1414-1430, Jun 2020. URL: https://doi.org/10.1261/rna.076430.120, doi:10.1261/rna.076430.120. This article has 46 citations and is from a domain leading peer-reviewed journal.
(latifi2024windowintothe pages 3-4): Shahrzad Latifi and A. Courtney DeVries. Window into the brain: in vivo multiphoton imaging. ACS Photonics, 12:1-15, Dec 2024. URL: https://doi.org/10.1021/acsphotonics.4c00958, doi:10.1021/acsphotonics.4c00958. This article has 5 citations and is from a domain leading peer-reviewed journal.
(zhang2023fastandsensitive pages 1-2): Yan Zhang, Márton Rózsa, Yajie Liang, Daniel Bushey, Ziqiang Wei, Jihong Zheng, Daniel Reep, Gerard Joey Broussard, Arthur Tsang, Getahun Tsegaye, Sujatha Narayan, Christopher J. Obara, Jing-Xuan Lim, Ronak Patel, Rongwei Zhang, Misha B. Ahrens, Glenn C. Turner, Samuel S.-H. Wang, Wyatt L. Korff, Eric R. Schreiter, Karel Svoboda, Jeremy P. Hasseman, Ilya Kolb, and Loren L. Looger. Fast and sensitive gcamp calcium indicators for imaging neural populations. Nature, 615:884-891, Nov 2023. URL: https://doi.org/10.1038/s41586-023-05828-9, doi:10.1038/s41586-023-05828-9. This article has 791 citations and is from a highest quality peer-reviewed journal.
(zhang2023fastandsensitive media 0c163603): Yan Zhang, Márton Rózsa, Yajie Liang, Daniel Bushey, Ziqiang Wei, Jihong Zheng, Daniel Reep, Gerard Joey Broussard, Arthur Tsang, Getahun Tsegaye, Sujatha Narayan, Christopher J. Obara, Jing-Xuan Lim, Ronak Patel, Rongwei Zhang, Misha B. Ahrens, Glenn C. Turner, Samuel S.-H. Wang, Wyatt L. Korff, Eric R. Schreiter, Karel Svoboda, Jeremy P. Hasseman, Ilya Kolb, and Loren L. Looger. Fast and sensitive gcamp calcium indicators for imaging neural populations. Nature, 615:884-891, Nov 2023. URL: https://doi.org/10.1038/s41586-023-05828-9, doi:10.1038/s41586-023-05828-9. This article has 791 citations and is from a highest quality peer-reviewed journal.
(hara2024highaffinitytuningof pages 1-2): Yusuke Hara, Aya Ichiraku, Tomoki Matsuda, Ayuko Sakane, Takuya Sasaki, Takeharu Nagai, and Kazuki Horikawa. High-affinity tuning of single fluorescent protein-type indicators by flexible linker length optimization in topology mutant. Communications Biology, Jun 2024. URL: https://doi.org/10.1038/s42003-024-06394-0, doi:10.1038/s42003-024-06394-0. This article has 6 citations and is from a peer-reviewed journal.
(gaido2023camkiiasa pages 20-21): Oscar E. Reyes Gaido, Lubika J. Nkashama, Kate L. Schole, Qinchuan Wang, Priya Umapathi, Olurotimi O. Mesubi, Klitos Konstantinidis, Elizabeth D. Luczak, and Mark E. Anderson. Camkii as a therapeutic target in cardiovascular disease. Annual Review of Pharmacology and Toxicology, 63:249-272, Jan 2023. URL: https://doi.org/10.1146/annurev-pharmtox-051421-111814, doi:10.1146/annurev-pharmtox-051421-111814. This article has 122 citations and is from a highest quality peer-reviewed journal.
(gruner2019preciseremovalof pages 35-37): Hannah N. Gruner, Bongmin Bae, Maebh Lynch, Daniel Oliver, Kevin So, Grant S. Mastick, Wei Yan, and Pedro Miura. Precise removal of calm1 long 3′ utr isoform by crispr-cas9 genome editing impairs dorsal root ganglion development in mice. bioRxiv, Feb 2019. URL: https://doi.org/10.1101/553990, doi:10.1101/553990. This article has 3 citations.
(gruner2019preciseremovalof pages 26-29): Hannah N. Gruner, Bongmin Bae, Maebh Lynch, Daniel Oliver, Kevin So, Grant S. Mastick, Wei Yan, and Pedro Miura. Precise removal of calm1 long 3′ utr isoform by crispr-cas9 genome editing impairs dorsal root ganglion development in mice. bioRxiv, Feb 2019. URL: https://doi.org/10.1101/553990, doi:10.1101/553990. This article has 3 citations.
(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 0 citations and is from a domain leading peer-reviewed journal.
(gruner2019preciseremovalof pages 1-4): Hannah N. Gruner, Bongmin Bae, Maebh Lynch, Daniel Oliver, Kevin So, Grant S. Mastick, Wei Yan, and Pedro Miura. Precise removal of calm1 long 3′ utr isoform by crispr-cas9 genome editing impairs dorsal root ganglion development in mice. bioRxiv, Feb 2019. URL: https://doi.org/10.1101/553990, doi:10.1101/553990. This article has 3 citations.
(steil2020thecalmodulinredox pages 1-2): 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.
(gonzalezramos2024updatedtoolboxfor pages 6-7): Ana Gonzalez-Ramos, Claudia Puigsasllosas-Pastor, Ainhoa Arcas-Marquez, and Daniel Tornero. Updated toolbox for assessing neuronal network reconstruction after cell therapy. Bioengineering, 11:487, May 2024. URL: https://doi.org/10.3390/bioengineering11050487, doi:10.3390/bioengineering11050487. This article has 4 citations.

Citations

sobue2024calmodulinahighly pages 1-2
gaido2023camkiiasa pages 25-28
rostas2023calciumcalmodulinstimulatedproteinkinase pages 1-2
chang2023identificationofnovel pages 2-4
nolze2023calcineurinisa pages 1-3
sobue2024calmodulinahighly pages 2-4
gruner2019preciseremovalof pages 4-8
latifi2024windowintothe pages 3-4
zhang2023fastandsensitive pages 1-2
hara2024highaffinitytuningof pages 1-2
tsai2025enrichmentofmutant pages 1-6
gaido2023camkiiasa pages 20-21
gruner2019preciseremovalof pages 35-37
gruner2019preciseremovalof pages 26-29
tsai2025enrichmentofmutant pages 6-10
gruner2019preciseremovalof pages 1-4
steil2020thecalmodulinredox pages 1-2
gonzalezramos2024updatedtoolboxfor pages 6-7
https://doi.org/10.2183/pjab.100.025
https://doi.org/10.1146/annurev-pharmtox-051421-111814
https://doi.org/10.3390/cells12030401
https://doi.org/10.3390/biomedicines11112891
https://doi.org/10.3390/cells12182269
https://doi.org/10.1101/553990;
https://doi.org/10.1261/rna.076430.120
https://doi.org/10.1038/s41586-023-05828-9
https://doi.org/10.1038/s42003-024-06394-0
https://doi.org/10.1261/rna.076430.120,
https://doi.org/10.1172/jci.insight.185524,
https://doi.org/10.2183/pjab.100.025,
https://doi.org/10.1146/annurev-pharmtox-051421-111814,
https://doi.org/10.3390/cells12030401,
https://doi.org/10.3390/biomedicines11112891,
https://doi.org/10.3390/cells12182269,
https://doi.org/10.1101/553990,
https://doi.org/10.1021/acsphotonics.4c00958,
https://doi.org/10.1038/s41586-023-05828-9,
https://doi.org/10.1038/s42003-024-06394-0,
https://doi.org/10.1371/journal.pone.0239047,
https://doi.org/10.3390/bioengineering11050487,

Notes

(Calm1-notes.md)

Calm1 Notes

2026-03-19

Calm1 encodes canonical calmodulin, a four-EF-hand calcium sensor whose sequence is shared with Calm2 and Calm3; the most defensible gene-specific distinctions for mouse Calm1 are regulatory rather than protein-sequence based [file:mouse/Calm1/Calm1-deep-research-falcon.md "Calm1's distinctive biological role is likely driven by mRNA-level regulation (APA-dependent UTRs, stability, and neuronal localization)"].
Cached literature supports broad core CaM functions rather than a narrow enzyme-like role: altered CaM levels change progression through G1 and mitosis in mouse cells PMID:2469574.
CaM directly modulates intracellular calcium-release pathways; IP3-receptor-mediated calcium mobilization is inhibited by calmodulin across receptor subtypes PMID:10620513.
CaM also behaves as a constitutive auxiliary channel subunit in neurons, with KCNQ2/3 current depending on CaM binding PMID:12223552.
Synaptic membrane trafficking is another supported non-core but plausible neuronal context: calmodulin knockout impaired multiple forms of endocytosis in hippocampal synapses PMID:31628181.
Mouse-specific follow-up worth keeping in mind for future review refinement: the deep-research summary points to Calm1-S and Calm1-L 3' UTR isoforms, with neural enrichment of the long isoform and phenotypes after distal poly(A) site deletion [file:mouse/Calm1/Calm1-deep-research-falcon.md "Calm1 has strong post-transcriptional regulation via alternative polyadenylation. It produces Calm1-S and Calm1-L transcripts with identical coding sequence but distinct 3' UTRs."].

Bioreason Rl Review

(Calm1-bioreason-rl-review.md)

BioReason-Pro RL Review: Calm1 (mouse)

Source: Calm1-deep-research-bioreason-rl.md

Correctness: 5/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary is accurate and well-articulated:

A soluble calcium-sensing regulator in mouse that uses multiple EF-hand motifs to bind Ca2+ and undergo conformational switching, thereby engaging diverse target proteins to transmit calcium signals. By toggling between Ca2+-bound and apo states, it modulates enzyme and cytoskeletal activities and influences nuclear programs. Its soluble architecture supports operation in the cytoplasm with functional access to the nucleus, where calcium-triggered binding events orchestrate downstream signaling pathways.

This correctly identifies: (1) the EF-hand-mediated calcium binding (GO:0005509), (2) the conformational switching between apo and Ca2+-bound states, (3) the downstream regulation of diverse targets, and (4) the cytoplasm/nucleus dual localization. The curated review confirms Calm1 as a "ubiquitous calcium-binding messenger protein" with four EF-hand domains that regulates "over 100 target proteins including kinases (CaMKII), phosphatases (calcineurin), ion channels (RyR1, RyR2, SCN8A), and cytoskeletal proteins (MYO5A)."

The mention of "enzyme and cytoskeletal activities" is a good generalization that encompasses CaMKII, calcineurin, and myosin interactions. The nuclear access is also correct -- the curated review notes Calm1 "redistributes to spindle poles and spindle microtubules during mitosis."

Minor gaps: The summary does not mention specific target classes (kinases, phosphatases, channels) or the role in cell cycle progression/cytokinesis, which is a notable curated function.

Comparison with interpro2go:

There are no GO_REF:0000002 annotations for Calm1 in the curated review. The BioReason GO term predictions include GO:0005509 (calcium ion binding), which matches the IBA annotation. BioReason's functional summary adds substantial value over what domain-based mappings alone would provide, particularly in describing the conformational switching mechanism and the breadth of target regulation. The predicted GO terms also include cell cycle-related terms (G2/M transition), which aligns with the curated review's emphasis on mitotic roles, suggesting BioReason captures more than basic domain-to-function mapping.

Notes on thinking trace

The trace correctly interprets the EF-hand pair architecture and the calmodulin/troponin C family classification. The reasoning about amphipathic target helix clamping (IQ and 1-8-14 motifs) shows good mechanistic understanding. The hypothesis about CaM-dependent kinases and phosphatases as partners is accurate.

📄 View Raw YAML

id: P0DP26
gene_symbol: Calm1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Calmodulin-1 is a ubiquitous calcium-binding messenger protein that serves
  as the primary intracellular calcium sensor in eukaryotic cells. Through its four
  EF-hand domains, Calm1 binds calcium ions and undergoes conformational changes enabling
  interaction with and regulation of over 100 target proteins including kinases (CaMKII),
  phosphatases (calcineurin), ion channels (RyR1, RyR2, SCN8A), and cytoskeletal proteins
  (MYO5A). Essential for calcium signal transduction, muscle contraction, cardiac
  function, cell cycle progression, and neurotransmission. Highly conserved - identical
  in sequence to human CALM1, CALM2, and CALM3. Localized primarily to cytoplasm but
  redistributes to spindle poles and spindle microtubules during mitosis for cytokinesis
  regulation.
existing_annotations:
- 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
- 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: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:0005813
    label: centrosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Centrosomal localization for cell division
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Spindle pole localization during mitosis
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Centrosomal localization for cell division
    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: ACCEPT
    reason: Core calmodulin function or localization
- 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:0031514
    label: motile cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Ciliary localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Parent term - too general
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- 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: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 regulation through ion channel modulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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: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: ACCEPT
    reason: Core calmodulin function or localization
- 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 regulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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: IQ motif and calmodulin-binding domain recognition
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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: Regulates NOS enzymes
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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: ACCEPT
    reason: Core calmodulin function or localization
- 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: Binds NOS for activation
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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 through calcium channel regulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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:0090150
    label: establishment of protein localization to membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Membrane protein localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0090151
    label: obsolete establishment of protein localization to mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Term is obsolete - should be removed
    action: REMOVE
    reason: GO term is obsolete
- 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: Part of enzyme complexes
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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:0000922
    label: spindle pole
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Spindle pole localization during mitosis
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0002027
    label: regulation of heart rate
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Heart rate regulation through ion channel modulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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: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: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: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Soluble cytosolic protein
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005876
    label: spindle microtubule
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Spindle microtubule association
    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 regulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0016240
    label: autophagosome membrane docking
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  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: 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: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: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:0032465
    label: regulation of cytokinesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cytokinesis regulation with CP110 and centrin
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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:0035458
    label: cellular response to interferon-beta
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Interferon-beta response
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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: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:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: JAK-STAT pathway regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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 through calcium channel regulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0060314
    label: regulation of ryanodine-sensitive calcium-release channel activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Regulates RyR1 and RyR2 activity
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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:0071346
    label: cellular response to type II interferon
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  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: 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:0098901
    label: regulation of cardiac muscle cell action potential
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cardiac action potential regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0140056
    label: organelle localization by membrane tethering
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Organelle membrane tethering
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1901842
    label: negative regulation of high voltage-gated calcium channel activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Calcium channel activity 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: ISO
  original_reference_id: GO_REF:0000119
  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: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Part of enzyme complexes
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1990456
    label: mitochondrion-endoplasmic reticulum membrane tethering
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ER-mitochondria contact regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Chromatin association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Nuclear localization in some contexts
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: JAK-STAT signaling pathway
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: IQ motif and calmodulin-binding domain recognition
    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: Regulates NOS enzymes
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  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: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Synaptic vesicle localization
    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: mGluR3 binding in neurons
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Mitochondrial membrane association
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Myelin sheath localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043548
    label: phosphatidylinositol 3-kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  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: ISO
  original_reference_id: GO_REF:0000096
  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: Binds NOS for activation
    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: Hippocampal synapse localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Presynaptic localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0099524
    label: postsynaptic cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Postsynaptic localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10620513
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
    supported_by:
    - reference_id: PMID:10620513
      supporting_text: Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2
        and -3 inositol trisphosphate receptors.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11955285
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
    supported_by:
    - reference_id: PMID:11955285
      supporting_text: Localization and function of a calmodulin-apocalmodulin-binding
        domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor.
- term:
    id: GO:0044305
    label: calyx of Held
  evidence_type: NAS
  original_reference_id: PMID:31628181
  review:
    summary: Calyx of Held synapse localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0044305
    label: calyx of Held
  evidence_type: IMP
  original_reference_id: PMID:31628181
  review:
    summary: Calyx of Held synapse localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0044305
    label: calyx of Held
  evidence_type: IDA
  original_reference_id: PMID:31628181
  review:
    summary: Calyx of Held synapse localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0140238
    label: presynaptic endocytosis
  evidence_type: NAS
  original_reference_id: PMID:31628181
  review:
    summary: Presynaptic vesicle endocytosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0140238
    label: presynaptic endocytosis
  evidence_type: IMP
  original_reference_id: PMID:31628181
  review:
    summary: Presynaptic vesicle endocytosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0140238
    label: presynaptic endocytosis
  evidence_type: IDA
  original_reference_id: PMID:31628181
  review:
    summary: Presynaptic vesicle endocytosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:31628181
      supporting_text: Epub 2019 Oct 18. Protein Kinase C and Calmodulin Serve As
        Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29025071
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
    supported_by:
    - reference_id: PMID:29025071
      supporting_text: The expression characteristics of FAM71D and its association
        with sperm motility.
- term:
    id: GO:0097225
    label: sperm midpiece
  evidence_type: IDA
  original_reference_id: PMID:29025071
  review:
    summary: Sperm midpiece localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
    supported_by:
    - reference_id: PMID:29025071
      supporting_text: The expression characteristics of FAM71D and its association
        with sperm motility.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31088288
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
    supported_by:
    - reference_id: PMID:31088288
      supporting_text: Epub 2019 Jun 24. The Axonal Motor Neuropathy-Related HINT1
        Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease.
- term:
    id: GO:0016240
    label: autophagosome membrane docking
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Autophagosome docking regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0140056
    label: organelle localization by membrane tethering
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Organelle membrane tethering
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:1990456
    label: mitochondrion-endoplasmic reticulum membrane tethering
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ER-mitochondria contact regulation
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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: Oct 24. Structural analysis of the complex between calmodulin
        and full-length myelin basic protein, an intrinsically disordered molecule.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9005848
  review:
    summary: Nucleoplasm localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9005872
  review:
    summary: Nucleoplasm localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9007015
  review:
    summary: Nucleoplasm localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-2025936
  review:
    summary: Soluble cytosolic protein
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-2316348
  review:
    summary: Soluble cytosolic protein
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-2316351
  review:
    summary: Soluble cytosolic protein
    action: ACCEPT
    reason: Core calmodulin function or localization
- 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:0060314
    label: regulation of ryanodine-sensitive calcium-release channel activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulates RyR1 and RyR2 activity
    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: 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.
- 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.
    - reference_id: file:mouse/Calm1/Calm1-deep-research-falcon.md
      supporting_text: Deep research synthesis supports Calm1 as a canonical four-EF-hand
        calcium sensor with gene-specific regulation dominated by transcript-level
        control rather than a distinct protein sequence.
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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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:10620513
  title: Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol
    trisphosphate receptors.
  findings: []
- id: PMID:11955285
  title: Localization and function of a calmodulin-apocalmodulin-binding domain in
    the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor.
  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:29025071
  title: The expression characteristics of FAM71D and its association with sperm motility.
  findings: []
- id: PMID:31088288
  title: The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated
    Cysteine SUMO Protease.
  findings: []
- id: PMID:31628181
  title: Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated
    Endocytosis at Synapses.
  findings: []
- id: file:mouse/Calm1/Calm1-deep-research-falcon.md
  title: Falcon deep research summary for mouse Calm1
  findings: []
- id: Reactome:R-MMU-2025936
  title: Calcineurin Dephosphorylates Nfatc2
  findings: []
- id: Reactome:R-MMU-2316348
  title: RalA:GTP binds Myo1c:Calm1 and F-actin
  findings: []
- id: Reactome:R-MMU-2316351
  title: Translocation of Glut4 Vesicle and Docking at the Plasma Membrane
  findings: []
- id: Reactome:R-MMU-9005848
  title: Active Prkaca and CaMK IV phosphorylate Mecp2 at T308
  findings: []
- id: Reactome:R-MMU-9005872
  title: Active Prkaca, CAMK IV does not phosphorylate Mecp2_e2 mutant R306C at T308
  findings: []
- id: Reactome:R-MMU-9007015
  title: Mecp2 is phosphorylated at S421
  findings: []
core_functions:
- description: Primary calcium-sensing protein that binds calcium ions through four
    EF-hand domains, undergoing conformational changes that enable interaction with
    over 100 target proteins.
  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:P0DP26
    supporting_text: Calmodulin mediates the control of a large number of enzymes,
      ion channels, aquaporins and other proteins through calcium-binding
- description: Regulates calcium-dependent protein kinases (CaMKII, CaMKIV) and phosphatases
    (calcineurin/PP2B) for signal transduction.
  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:P0DP26
    supporting_text: Among the enzymes to be stimulated by the calmodulin-calcium
      complex are a number of protein kinases and phosphatases
- description: Regulates ryanodine receptors (RyR1, RyR2) and IP3 receptors for calcium
    release from intracellular stores, essential for cardiac and skeletal muscle function.
  molecular_function:
    id: GO:0005246
    label: calcium channel regulator activity
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  supported_by:
  - reference_id: PMID:10620513
    supporting_text: Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2
      and -3 inositol trisphosphate receptors
- description: Localizes to centrosomes and spindle during mitosis, regulating cytokinesis
    through interaction with CP110 and centrin.
  molecular_function:
    id: GO:0019901
    label: protein kinase binding
  locations:
  - id: GO:0005813
    label: centrosome
  - id: GO:0000922
    label: spindle pole
  directly_involved_in:
  - id: GO:0032465
    label: regulation of cytokinesis
  - id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  supported_by:
  - reference_id: UniProtKB:P0DP26
    supporting_text: Together with CCP110 and centrin, is involved in a genetic pathway
      that regulates the centrosome cycle and progression through cytokinesis

Calm1

Gene Description

Existing Annotations Review

Core Functions

Primary calcium-sensing protein that binds calcium ions through four EF-hand domains, undergoing conformational changes that enable interaction with over 100 target proteins.

Regulates calcium-dependent protein kinases (CaMKII, CaMKIV) and phosphatases (calcineurin/PP2B) for signal transduction.

Regulates ryanodine receptors (RyR1, RyR2) and IP3 receptors for calcium release from intracellular stores, essential for cardiac and skeletal muscle function.

Localizes to centrosomes and spindle during mitosis, regulating cytokinesis through interaction with CP110 and centrin.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

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:

Research Report: Mouse Calm1 (UniProt P0DP26) / Calmodulin-1

Scope and identity verification (MANDATORY)

1) Key concepts and definitions (current understanding)

Calmodulin (CaM) as a Ca2+ “sensor/transducer”

EF-hand structure and Ca2+-binding sites

Physiological Ca2+ regime CaM is tuned for

2) Recent developments and latest research (prioritizing 2023–2024)

2024: Consolidated modern view of CaM as a “master Ca2+ decoder”

2023: CaM-dependent CaMKII as an actionable therapeutic axis

2023–2024: Mechanistic refinement of CaMKII activation logic

2023: CaM requirement in calcineurin/CaMKII control of an ion channel (example: Cav3.2)

3) Primary function, biological processes, and major pathways

Primary molecular function

Major downstream pathways and target classes

4) Mouse Calm1-specific regulation, localization, and phenotypes

Alternative polyadenylation (APA) creates two Calm1 3′-UTR isoforms

Tissue enrichment of Calm1-L in neural tissues

Subcellular localization differences in DRG neurons

RNA stability differences

In vivo phenotypes from isoform-specific perturbation

5) Current applications and real-world implementations

CaM as an engineered module in GCaMP-type genetically encoded Ca2+ indicators (GECIs)

2023 Nature: jGCaMP8 enables millisecond-timescale population imaging

2024 engineering: ultrahigh-affinity CaM-based indicators

6) Expert opinion and analysis (authoritative synthesis)

7) Relevant statistics and recent data highlights (selected)

Summary table (evidence map)

Retrieved figure (visual evidence)

Citations

Notes

Calm1 Notes

2026-03-19

Bioreason Rl Review

BioReason-Pro RL Review: Calm1 (mouse)

Functional Summary Review

Notes on thinking trace

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