Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization Supporting Evidence: file:human/CALM3/CALM3-deep-research-falcon.md CaM has two homologous globular domains (N- and C-lobes) connected by a flexible central helix; each lobe contains two canonical EF-hand helix-loop-helix motifs, yielding four Ca2+ binding sites per CaM molecule.
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 Supporting Evidence: file:human/CALM3/CALM3-deep-research-falcon.md Calmodulin is a ubiquitously expressed Ca2+ sensor that transduces intracellular Ca2+ changes into functional regulation of diverse target proteins.
GO:0097720 calcineurin-mediated signaling	IBA GO_REF:0000033	ACCEPT	Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization
GO:0005813 centrosome	IBA GO_REF:0000033	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:0000922 spindle pole	IEA GO_REF:0000120	ACCEPT	Summary: Spindle pole localization during mitosis Reason: Core calmodulin function or localization
GO:0002027 regulation of heart rate	IEA GO_REF:0000117	ACCEPT	Summary: Heart rate regulation through ion channel modulation Reason: Retained as core because the annotation reflects direct calmodulin control of cardiac ion-channel and calcium-release machinery; broader downstream electrophysiology terms are kept non-core separately.
GO:0005246 calcium channel regulator activity	IEA GO_REF:0000117	ACCEPT	Summary: Regulates L-type calcium channels and ryanodine receptors Reason: Core calmodulin function or localization Supporting Evidence: file:human/CALM3/CALM3-deep-research-falcon.md CaM is pre-associated with CaV1.2, and C-lobe EF-hand mutations that reduce Ca2+ binding can blunt calcium-dependent inactivation, increasing Ca2+ entry and prolonging action potentials.
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:0005513 detection of calcium ion	IEA GO_REF:0000117	ACCEPT	Summary: Core calcium sensing function 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:0005876 spindle microtubule	IEA GO_REF:0000117	ACCEPT	Summary: Spindle microtubule association Reason: Core calmodulin function or localization
GO:0010856 adenylate cyclase activator activity	IEA GO_REF:0000117	ACCEPT	Summary: Activates adenylate cyclase for cAMP signaling 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:0000117	ACCEPT	Summary: Cardiac calcium-induced calcium release regulation Reason: Retained as core because regulation of sequestered calcium release maps directly to calmodulin-RyR/SR calcium-release control, a core channel-regulatory mechanism despite the cardiac wording.
GO:0019901 protein kinase binding	IEA GO_REF:0000117	ACCEPT	Summary: Binds CaMK family and other protein kinases Reason: Core calmodulin function or localization
GO:0030017 sarcomere	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Sarcomere localization in muscle Reason: Tissue-specific or specialized function
GO:0031432 titin binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Titin binding in muscle Reason: Tissue-specific or specialized function
GO:0032465 regulation of cytokinesis	IEA GO_REF:0000117	ACCEPT	Summary: Cytokinesis regulation with CP110 and centrin Reason: Core calmodulin function or localization
GO:0034704 calcium channel complex	IEA GO_REF:0000117	ACCEPT	Summary: Component of calcium channel complexes Reason: Core calmodulin function or localization
GO:0043539 protein serine/threonine kinase activator activity	IEA GO_REF:0000117	ACCEPT	Summary: Activates CaMKII and other calcium-dependent kinases Reason: Core calmodulin function or localization
GO:0060291 long-term synaptic potentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Long-term synaptic potentiation reflects specialized neuronal signaling. Reason: Calmodulin is important for synaptic plasticity, but this is a tissue-specific downstream context and should not be used to distinguish CALM3 from CALM1 or CALM2.
GO:0072542 protein phosphatase activator activity	IEA GO_REF:0000117	ACCEPT	Summary: Activates calcineurin (PP2B) phosphatase Reason: Core calmodulin function or localization
GO:0097720 calcineurin-mediated signaling	IEA GO_REF:0000117	ACCEPT	Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization
GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Cardiac electrical coupling regulation Reason: Tissue-specific or specialized function
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
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:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Nuclear localization in some contexts Reason: Tissue-specific or specialized function
GO:0008076 voltage-gated potassium channel complex	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: KCNQ channel complex component Reason: Tissue-specific or specialized function
GO:0016020 membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: General membrane localization is plausible but not a core assignment. Reason: Calmodulin is recruited to membrane-associated channels and receptors, but broad membrane localization is secondary to its core soluble calcium-sensor role.
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: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: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:0031982 vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Vesicle association is observed in specialized trafficking or exosome contexts. Reason: Vesicle localization reflects specific cell-type and trafficking contexts rather than a defining family-wide localization for the identical calmodulin protein.
GO:0043209 myelin sheath	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Myelin sheath localization Reason: Tissue-specific or specialized function
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:0044305 calyx of Held	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Calyx of Held synapse localization 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: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:0097225 sperm midpiece	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Sperm midpiece localization Reason: Tissue-specific or specialized function
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: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:0140238 presynaptic endocytosis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Presynaptic vesicle endocytosis Reason: Tissue-specific or specialized function
GO:0141110 transporter inhibitor activity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This term is too specific for the available transfer evidence. Reason: Calmodulin modulates multiple transporters and channels, but a generic transporter inhibitor term overstates a context-dependent regulatory effect.
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:1905913 negative regulation of calcium ion export across plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Negative regulation of calcium export is plausible in channel-regulatory contexts but not a core assignment. Reason: This term reflects a specific downstream physiological setting of calmodulin-dependent channel regulation rather than a defining family-wide process.
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:0005829 cytosol	TAS Reactome:R-HSA-9956602	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0005829 cytosol	TAS Reactome:R-HSA-9956624	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0005829 cytosol	TAS Reactome:R-HSA-9956667	ACCEPT	Summary: Soluble cytosolic protein Reason: Core calmodulin function or localization
GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	IDA PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Cardiac calcium-induced calcium release regulation Reason: Retained as core because PMID:23040497 directly supports calmodulin regulation of RyR-mediated sarcoplasmic-reticulum calcium release; broader cardiac electrophysiology phenotypes are treated as non-core.
GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction	IDA PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	KEEP AS NON CORE	Summary: Cardiac electrical coupling regulation Reason: Kept non-core because cardiac electrical coupling is a downstream tissue-level conduction phenotype rather than the direct calmodulin biochemical mechanism, which is captured by calcium/channel regulatory terms.
GO:0005246 calcium channel regulator activity	IDA PMID:20226167 Defective calmodulin binding to the cardiac ryanodine recept...	ACCEPT	Summary: Regulates L-type calcium channels and ryanodine receptors Reason: Core calmodulin function or localization
GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	IDA PMID:20226167 Defective calmodulin binding to the cardiac ryanodine recept...	ACCEPT	Summary: Cardiac calcium-induced calcium release regulation Reason: Core calmodulin function or localization
GO:0060291 long-term synaptic potentiation	TAS PMID:20668654 Structure of the CaMKIIdelta/calmodulin complex reveals the ...	KEEP AS NON CORE	Summary: Long-term synaptic potentiation reflects specialized neuronal signaling. Reason: Calmodulin is important for synaptic plasticity, but this is a tissue-specific downstream context and should not be used to distinguish CALM3 from CALM1 or CALM2.
GO:0097720 calcineurin-mediated signaling	IDA PMID:8631777 Blocking the Ca2+-induced conformational transitions in calm...	ACCEPT	Summary: Activates calcineurin phosphatase for NFAT signaling Reason: Core calmodulin function or localization
GO:0005515 protein binding	IPI PMID:11984006 The Chediak-Higashi protein interacts with SNARE complex and...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:19855925 Structural analysis of the complex between calmodulin and fu...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005509 calcium ion binding	IDA PMID:35568036 A family of conserved bacterial virulence factors dampens in...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0043539 protein serine/threonine kinase activator activity	IDA PMID:35568036 A family of conserved bacterial virulence factors dampens in...	ACCEPT	Summary: Activates CaMKII and other calcium-dependent kinases Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:31454269 Genetic Mosaicism in Calmodulinopathy.	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0098901 regulation of cardiac muscle cell action potential	IMP PMID:31454269 Genetic Mosaicism in Calmodulinopathy.	KEEP AS NON CORE	Summary: Cardiac action potential regulation Reason: Kept non-core because action-potential regulation is a cardiac electrophysiology endpoint downstream of calmodulin control of CaV/RyR channels, not a distinct core molecular function.
GO:1901842 negative regulation of high voltage-gated calcium channel activity	IMP PMID:31454269 Genetic Mosaicism in Calmodulinopathy.	ACCEPT	Summary: Calcium channel activity regulation Reason: Accepted as direct channel regulation because PMID:31454269 supports impaired calcium-dependent inactivation of L-type calcium channels by calmodulin variants; this is closer to the core mechanism than the downstream action-potential phenotype.
GO:0010856 adenylate cyclase activator activity	IDA PMID:11807546 Structural basis for the activation of anthrax adenylyl cycl...	ACCEPT	Summary: Activates adenylate cyclase for cAMP signaling Reason: Core calmodulin function or localization
GO:0034704 calcium channel complex	IDA PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Component of calcium channel complexes Reason: Core calmodulin function or localization
GO:0000922 spindle pole	IDA PMID:16760425 CP110 cooperates with two calcium-binding proteins to regula...	ACCEPT	Summary: Spindle pole localization during mitosis Reason: Core calmodulin function or localization
GO:0005515 protein binding	IPI PMID:10692436 Ca(2+)-dependent and Ca(2+)-independent calmodulin binding s...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:15140941 Ca2+-binding protein-1 facilitates and forms a postsynaptic ...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:15632291 Myristoyl moiety of HIV Nef is involved in regulation of the...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:16760425 CP110 cooperates with two calcium-binding proteins to regula...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:21299499 IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of ...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005515 protein binding	IPI PMID:3111527 Comparison of S100b protein with calmodulin: interactions wi...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Nuclear localization in some contexts Reason: Tissue-specific or specialized function
GO:0005737 cytoplasm	TAS PMID:10899953 Calmodulin regulation of basal and agonist-stimulated G prot...	ACCEPT	Summary: Primary cytoplasmic localization Reason: Core calmodulin function or localization
GO:0005813 centrosome	IDA PMID:16760425 CP110 cooperates with two calcium-binding proteins to regula...	ACCEPT	Summary: Centrosomal localization for cell division Reason: Core calmodulin function or localization
GO:0005876 spindle microtubule	IDA PMID:16760425 CP110 cooperates with two calcium-binding proteins to regula...	ACCEPT	Summary: Spindle microtubule association Reason: Core calmodulin function or localization
GO:0005886 plasma membrane	TAS PMID:10899953 Calmodulin regulation of basal and agonist-stimulated G prot...	KEEP AS NON CORE	Summary: Plasma membrane association occurs in specific signaling contexts. Reason: Calmodulin can associate with membrane-proximal receptor and channel complexes, but plasma membrane residence is context dependent rather than a defining family-wide localization.
GO:0007186 G protein-coupled receptor signaling pathway	TAS PMID:10899953 Calmodulin regulation of basal and agonist-stimulated G prot...	KEEP AS NON CORE	Summary: Calmodulin modulates selected GPCR signaling pathways in specialized contexts. Reason: This captures a real signaling interaction, but the evidence is receptor- and context-specific and should not be treated as a defining CALM3 function relative to the other calmodulin paralogs.
GO:0021762 substantia nigra development	HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in...	REMOVE	Summary: Proteomic detection in substantia nigra does not justify a developmental annotation. Reason: The cited evidence is expression/proteomics in diseased tissue, not functional evidence for substantia nigra development.
GO:0031982 vesicle	HDA PMID:19190083 Characterization of exosome-like vesicles released from huma...	KEEP AS NON CORE	Summary: Vesicle association is observed in specialized trafficking or exosome contexts. Reason: Vesicle localization reflects specific cell-type and trafficking contexts rather than a defining family-wide localization for the identical calmodulin protein.
GO:0032465 regulation of cytokinesis	IMP PMID:16760425 CP110 cooperates with two calcium-binding proteins to regula...	ACCEPT	Summary: Cytokinesis regulation with CP110 and centrin Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:11807546 Structural basis for the activation of anthrax adenylyl cycl...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0008179 adenylate cyclase binding	IPI PMID:11807546 Structural basis for the activation of anthrax adenylyl cycl...	KEEP AS NON CORE	Summary: Direct adenylate cyclase binding is supported, but mainly in host-pathogen interaction studies. Reason: The interaction is real biochemistry for calmodulin, but the cited evidence centers on bacterial edema-factor activation rather than a defining endogenous CALM3 role.
GO:0032991 protein-containing complex	IDA PMID:19855925 Structural analysis of the complex between calmodulin and fu...	MARK AS OVER ANNOTATED	Summary: Too general - more specific terms available Reason: Too general - more specific terms are available
GO:1902494 catalytic complex	IDA PMID:11807546 Structural basis for the activation of anthrax adenylyl cycl...	KEEP AS NON CORE	Summary: Part of enzyme complexes Reason: Tissue-specific or specialized function
GO:0002027 regulation of heart rate	IMP PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Heart rate regulation through ion channel modulation Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:7607248 A calmodulin-binding sequence in the C-terminus of human car...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:8631777 Blocking the Ca2+-induced conformational transitions in calm...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization
GO:0005513 detection of calcium ion	IMP PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Core calcium sensing function Reason: Core calmodulin function or localization
GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	IDA PMID:20226167 Defective calmodulin binding to the cardiac ryanodine recept...	ACCEPT	Summary: Regulates RyR-mediated calcium release from SR Reason: Core calmodulin function or localization
GO:0019901 protein kinase binding	IPI PMID:20668654 Structure of the CaMKIIdelta/calmodulin complex reveals the ...	ACCEPT	Summary: Binds CaMK family and other protein kinases Reason: Core calmodulin function or localization
GO:0030017 sarcomere	IDA PMID:20226167 Defective calmodulin binding to the cardiac ryanodine recept...	KEEP AS NON CORE	Summary: Sarcomere localization in muscle Reason: Tissue-specific or specialized function
GO:0031432 titin binding	IPI PMID:7607248 A calmodulin-binding sequence in the C-terminus of human car...	KEEP AS NON CORE	Summary: Titin binding in muscle Reason: Tissue-specific or specialized function
GO:0043539 protein serine/threonine kinase activator activity	TAS PMID:20668654 Structure of the CaMKIIdelta/calmodulin complex reveals the ...	ACCEPT	Summary: Activates CaMKII and other calcium-dependent kinases Reason: Core calmodulin function or localization
GO:0044325 transmembrane transporter binding	IPI PMID:21167176 Solution NMR structure of Apo-calmodulin in complex with the...	ACCEPT	Summary: Binds ion channels and transporters Reason: Core calmodulin function or localization
GO:0044325 transmembrane transporter binding	IPI PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Binds ion channels and transporters Reason: Core calmodulin function or localization
GO:0051592 response to calcium ion	IDA PMID:7607248 A calmodulin-binding sequence in the C-terminus of human car...	KEEP AS NON CORE	Summary: Response to calcium ion Reason: Tissue-specific or specialized function
GO:0055117 regulation of cardiac muscle contraction	IMP PMID:23040497 Mutations in calmodulin cause ventricular tachycardia and su...	ACCEPT	Summary: Cardiac contraction through calcium channel regulation Reason: Retained as core because the evidence links calmodulin to cardiac contraction through direct RyR/calcium-channel regulation; broader tissue-level electrical-conduction phenotypes remain non-core.
GO:0072542 protein phosphatase activator activity	IDA PMID:8631777 Blocking the Ca2+-induced conformational transitions in calm...	ACCEPT	Summary: Activates calcineurin (PP2B) phosphatase Reason: Core calmodulin function or localization
GO:0005509 calcium ion binding	IDA PMID:27516456 Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A1...	ACCEPT	Summary: Core calcium-binding function through 4 EF-hand domains Reason: Core calmodulin function or localization

Core Functions

Primary intracellular calcium sensor. CALM3-encoded calmodulin binds calcium through four EF-hand motifs and converts calcium fluctuations into target-protein regulation.

Molecular Function:

calcium ion binding

Directly Involved In:

detection of calcium ion

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:27516456
Humans have 3 CaM genes ( CALM1 , CALM2 , and CALM3 ) encoding for a perfectly conserved sequence of amino acids
PMID:23040497
Both CALM1 substitutions demonstrated compromised calcium binding
file:human/CALM3/CALM3-deep-research-falcon.md
CaM has two homologous globular domains (N- and C-lobes) connected by a flexible central helix; each lobe contains two canonical EF-hand helix-loop-helix motifs, yielding four Ca2+ binding sites per CaM molecule.

Core calcium-dependent signal-transduction adaptor for kinase and phosphatase regulation, especially CaMK and calcineurin pathways.

Molecular Function:

protein serine/threonine kinase activator activity

Directly Involved In:

calcineurin-mediated signaling

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:20668654
Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation.
PMID:35568036
IFN inhibition was mediated by the binding of OspC1 and OspC3 to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II
PMID:8631777
Blocking the Ca2+-induced conformational transitions in calmodulin with disulfide bonds.
file:human/CALM3/CALM3-deep-research-falcon.md
Ca2+/CaM activates CaMKII and calcineurin, linking CaM to phosphorylation/dephosphorylation cascades.

Regulator of cardiac and other excitable-cell calcium channels, especially RyR2 and high-voltage-gated calcium-channel pathways.

Molecular Function:

calcium channel regulator activity

Directly Involved In:

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

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:20226167
the addition of a high concentration of CaM attenuated the aberrant increase of Ca(2+) sparks
PMID:27516456
A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity
PMID:31454269
Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca2+-dependent inactivation of L-type Ca2+ channels and prolonged action potential duration
file:human/CALM3/CALM3-deep-research-falcon.md
CaM regulates intracellular Ca2+ release channels. Notably, RyR2 is inhibited by both apoCaM and Ca2+/CaM.

Centrosome-associated regulator of late cytokinesis through CP110/centrin-containing cell-division machinery.

Molecular Function:

protein kinase binding

Directly Involved In:

regulation of cytokinesis

Cellular Locations:

centrosome spindle pole

Supporting Evidence:

PMID:16760425
its depletion leads to a failure at a late stage of cytokinesis and the formation of binucleate cells

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF: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:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10692436

Ca(2+)-dependent and Ca(2+)-independent calmodulin binding sites in erythrocyte protein 4.1. Implications for regulation of protein 4.1 interactions with transmembrane proteins.

PMID:10899953

Calmodulin regulation of basal and agonist-stimulated G protein coupling by the mu-opioid receptor (OP(3)) in morphine-pretreated cell.

PMID:11807546

Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin.

PMID:11984006

The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins.

PMID:15140941

Ca2+-binding protein-1 facilitates and forms a postsynaptic complex with Cav1.2 (L-type) Ca2+ channels.

PMID:15632291

Myristoyl moiety of HIV Nef is involved in regulation of the interaction with calmodulin in vivo.

PMID:16760425

CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability.

PMID:19190083

Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense.

PMID:19855925

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

PMID:20226167

Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction.

PMID:20668654

Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation.

PMID:21167176

Solution NMR structure of Apo-calmodulin in complex with the IQ motif of human cardiac sodium channel NaV1.5.

PMID:21299499

IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and myosin essential light chain.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:22926577

Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.

PMID:23040497

Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.

PMID:27516456

Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks.

PMID:3111527

Comparison of S100b protein with calmodulin: interactions with melittin and microtubule-associated tau proteins and inhibition of phosphorylation of tau proteins by protein kinase C.

PMID:31454269

Genetic Mosaicism in Calmodulinopathy.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35568036

A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling.

PMID:7607248

A calmodulin-binding sequence in the C-terminus of human cardiac titin kinase.

PMID:8631777

Blocking the Ca2+-induced conformational transitions in calmodulin with disulfide bonds.

Reactome:R-HSA-9956602

CALM binds bacterial OspC3

Reactome:R-HSA-9956624

OspC3 ADP-riboxanates CASP4

Reactome:R-HSA-9956667

CASP4 binds CALM:OspC3

PMID:9681195

Characterization of the human CALM2 calmodulin gene and comparison of the transcriptional activity of CALM1, CALM2 and CALM3.

file:human/CALM3/CALM3-notes.md

Curator notes for CALM3 review

file:human/CALM3/CALM3-deep-research-falcon.md

Falcon deep research report for CALM3

Falcon research supports CALM3 as one of three human genes encoding identical calmodulin, a four-EF-hand calcium sensor that regulates target proteins including CaMKII, calcineurin, voltage-gated calcium channels, and ryanodine receptors.

"three distinct human genes (CALM1, CALM2, CALM3) encode identical 149-aa calmodulin (CaM) protein sequences"

Deep Research

Falcon

(CALM3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2026-05-10T20:11:51.248458

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.

Research report: Human CALM3 (UniProt P0DP25) — functional annotation, pathways, and clinical relevance

0) Verification of correct gene/protein identity (critical)

CALM3 (UniProt accession P0DP25) corresponds to human calmodulin-3, a canonical member of the calmodulin family (EF-hand Ca2+-binding protein). Multiple authoritative sources explicitly state that three distinct human genes (CALM1, CALM2, CALM3) encode identical 149-aa calmodulin (CaM) protein sequences, despite being located on different chromosomes. This resolves gene-symbol ambiguity and confirms that literature discussing human “calmodulin/CaM” protein function generally applies directly to CALM3’s protein product. (hussey2023calmodulinmutationsin pages 1-2, jensen2024calmodulinvariantsin pages 10-12)

1) Key concepts and definitions (current understanding)

1.1 What CALM3 encodes: a Ca2+ sensor (not an enzyme)

Calmodulin (CaM) is a ubiquitously expressed Ca2+ sensor that transduces intracellular Ca2+ changes into functional regulation of diverse target proteins; it does not catalyze a chemical reaction. It is a small (~17 kDa), 149-amino-acid protein present in essentially all eukaryotic cells. (hussey2023calmodulinmutationsin pages 1-2)

1.2 Core structural definition: EF-hands and two lobes

CaM has two homologous globular domains (N- and C-lobes) connected by a flexible central helix; each lobe contains two canonical EF-hand helix–loop–helix motifs, yielding four Ca2+ binding sites per CaM molecule. (hussey2023calmodulinmutationsin pages 1-2, sobue2024calmodulinahighly pages 1-2)

A structural analysis of many CaM–target complexes emphasizes conserved target-recognition principles (hydrophobic anchor residues in targets and methionine-rich interaction surfaces in CaM), supporting how CaM can bind many different partners using common physical interaction modes. (denesyuk2023canonicalstructuralbindingmodes pages 24-27)

1.3 Calcium-binding mechanism and Ca2+-triggered switching

In resting cells, cytosolic free Ca2+ is ~10^-7 M, whereas extracellular Ca2+ is ~10^-3 M (a ~10,000-fold gradient). Upon stimulation, cytosolic Ca2+ can rise to ~10^-6–10^-5 M. These Ca2+ rises are the physiological signals that CaM detects via its EF-hands. (sobue2024calmodulinahighly pages 1-2)

Ca2+ saturation of CaM is associated with conformational changes that expose hydrophobic surfaces and enable productive binding to target proteins, providing a mechanistic link between Ca2+ signals and downstream regulation. (sobue2024calmodulinahighly pages 1-2)

1.4 Quantitative Ca2+ binding properties (biophysical “definition” of lobe asymmetry)

A mechanistically important feature is that the N- and C-lobes differ in Ca2+ affinity. One recent review reports approximate dissociation constants (KD) of ~16 µM (N-lobe) and ~2.4 µM (C-lobe), enabling partially separable “lobe-specific” regulation of targets. (hussey2023calmodulinmutationsin pages 1-2)

Another recent review summarizes CaM Ca2+ affinity in the ~5×10^-7 to 5×10^-6 M range and estimates intracellular CaM concentrations in mammalian cells at ~2–10 µM, placing CaM in the concentration regime where it can act as a high-capacity Ca2+ signal decoder. (sobue2024calmodulinahighly pages 1-2)

2) Primary biological function, pathways, and mechanisms of action

2.1 Primary function: regulate targets by apoCaM pre-association and Ca2+-dependent switching

A central modern concept is that many targets are pre-associated with Ca2+-free calmodulin (apoCaM), so CaM acts as a “resident” Ca2+ sensor at the target. Upon Ca2+ binding, CaM changes binding mode and/or conformation, producing functional modulation such as feedback inhibition or facilitation. (hussey2023calmodulinmutationsin pages 2-4)

Disease-associated EF-hand mutations can alter Ca2+ binding without disrupting the Ca2+-free structure, preserving apo-association but impairing Ca2+-dependent regulation—an important mechanistic explanation for dominant-negative effects in heterozygous patients. (hussey2023calmodulinmutationsin pages 2-4)

2.2 Canonical and high-confidence pathways/targets relevant to functional annotation

Voltage-gated Ca2+ channels (CaV1.x / CaV2.x): CaM frequently binds an IQ motif in the channel C-terminus. Ca2+ binding to CaM then drives calcium-dependent inactivation (CDI) and/or calcium-dependent facilitation (CDF), with strong lobe-specificity in several channels (e.g., CaV2.2/2.3 CDI driven by N-lobe; L-type channels can involve either lobe depending on context). (hussey2023calmodulinmutationsin pages 2-4)

CaV1.2 (cardiac L-type Ca2+ channel) is emphasized as a key pathogenic substrate in calmodulinopathy: CaM is pre-associated with CaV1.2, and C-lobe EF-hand mutations that reduce Ca2+ binding can blunt CDI, increasing Ca2+ entry and prolonging action potentials (a mechanistic route to LQTS). (hussey2023calmodulinmutationsin pages 9-11)

Ryanodine receptors (RyR1/RyR2): CaM regulates intracellular Ca2+ release channels. Notably, RyR2 (cardiac) is inhibited by both apoCaM and Ca2+/CaM; the C-lobe of Ca2+/CaM can increase the termination threshold of spontaneous Ca2+ release, indicating state- and lobe-specific control of Ca2+ sparks/waves. (hussey2023calmodulinmutationsin pages 4-6)

SK (small-conductance Ca2+-activated K+) channels: CaM is constitutively associated and required for gating; one review notes four CaM molecules per channel and indicates that CaM’s N-lobe drives Ca2+ dependence for SK2. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 4-6)

CaMKII and calcineurin/NFAT signaling: Ca2+/CaM activates CaMKII and calcineurin, linking CaM to phosphorylation/dephosphorylation cascades. CaMKII phosphorylates proteins central to excitation–contraction coupling (e.g., RyR2, L-type channels, phospholamban/SERCA regulation), and calcineurin can drive NFAT dephosphorylation and transcriptional signaling. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 1-2)

IP3 receptors (IP3R): CaM can decrease IP3 sensitivity in type I IP3R, with both apoCaM and Ca2+/CaM reported to reduce receptor sensitivity. (hussey2023calmodulinmutationsin pages 4-6)

Broader interaction landscape: A structural survey of CaM–target complexes (spanning apo and Ca2+-bound states) includes many relevant targets (e.g., CaMKII, calcineurin/PP2B, NaV1.5, RyR2, SK channels, MLCK), reinforcing the concept that CaM uses a conserved physical binding toolkit to regulate diverse pathways. (denesyuk2023canonicalstructuralbindingmodes pages 24-27)

3) Subcellular localization: where CALM3’s protein product acts

CaM is an intracellular protein and functions at the cytosolic faces of target proteins (e.g., cytosolic C-tails of ion channels) and at intracellular membranes where channels like RyR/IP3R reside. It is broadly distributed across tissues (and by implication across many cellular compartments where its targets are located), with estimated intracellular concentration ~2–10 µM. (sobue2024calmodulinahighly pages 1-2, hussey2023calmodulinmutationsin pages 4-6, hussey2023calmodulinmutationsin pages 2-4)

4) Disease relevance of CALM3: calmodulinopathy and variant mechanisms

4.1 Disease entity and phenotypes

Dominant pathogenic variants in any of CALM1/2/3 (including CALM3) cause calmodulinopathy, classically presenting as CALM-LQTS and/or CALM-CPVT, with additional presentations including idiopathic ventricular fibrillation and syndromic features. (hussey2023calmodulinmutationsin pages 4-6, crotti2023clinicalpresentationof pages 8-9)

A large 2023 update from the International Calmodulinopathy Registry (ICalmR) (European Heart Journal; published Aug 2023) provides the most authoritative recent clinical synthesis:
- N = 140 subjects total (97 index cases, 43 family members); median age 10.8 years (IQR 5–19). (crotti2023clinicalpresentationof pages 2-3)
- Phenotype proportions: CALM-LQTS 74 (53%), CALM-CPVT 36 (26%), LQTS/CPVT overlap 10 (7%), IVF 7 (5%), uncertain diagnosis 11 (8%), atypical 2 (1%). (crotti2023clinicalpresentationof pages 3-4)
- Symptomatic/arrhythmic events: 103 symptomatic patients (74%). (crotti2023clinicalpresentationof pages 2-3)
- Compared with an earlier 2019 cohort, all cardiac events decreased 85% → 61% (P=0.001) and sudden death decreased 27% → 9% (P=0.008), suggesting improving outcomes with broader recognition and management, while emphasizing that disease remains high-risk. (crotti2023clinicalpresentationof pages 2-3)

4.2 Variant clustering and molecular interpretation

In ICalmR, 58/62 variants were classified pathogenic/likely pathogenic by ACMG curation, and 49/58 (84%) clustered in exons 5–6, consistent with enrichment in C-lobe EF-hand regions central to Ca2+ chelation and target regulation. (crotti2023clinicalpresentationof pages 8-9)

Mechanistically, the registry notes that many LQTS-associated CALM variants map to EF-hands III/IV and reduce C-domain Ca2+ binding, impairing CaM-mediated CaV1.2 CDI (prolonging repolarization). (crotti2023clinicalpresentationof pages 12-13)

4.3 Extra-cardiac manifestations (interpretation and caution)

ICalmR also documents neurological involvement: among 111 evaluable patients, 35 had neurological disorders, including 20 primary neurological manifestations (not attributable to post-anoxic injury). (crotti2023clinicalpresentationof pages 3-4, crotti2023clinicalpresentationof pages 2-3)

Separately, a 2024 preprint reported enrichment of ultra-rare CALM missense variants in schizophrenia cases vs controls, with all case variants in the C-lobe and an estimated odds ratio ~5.6 for carrying a C-lobe variant; the authors also identify functional classes (reduced vs increased Ca2+ affinity). This is not yet as clinically established as the cardiac calmodulinopathy literature and should be interpreted as emerging evidence. (jensen2024calmodulinvariantsin pages 10-12, jensen2024calmodulinvariantsin pages 3-5)

5) Current applications and real-world implementations

5.1 Diagnostic implementation: genetic testing and registry-guided practice

A major real-world development is the formalization and expansion of the International Calmodulinopathy Registry, which has nearly doubled enrolled cases since its initial report and is used to clarify genotype–phenotype variability and outcomes. (crotti2023clinicalpresentationof pages 4-4, crotti2023clinicalpresentationof pages 2-3)

The ICalmR authors state that CALM1–3 are definitively associated with LQTS and CPVT and “should be screened in all LQTS and CPVT patients,” supporting routine inclusion of CALM genes on clinical genetic testing panels. (crotti2023clinicalpresentationof pages 4-4)

5.2 Management approaches documented in contemporary cohorts

ICalmR reports that contemporary management commonly includes pharmacological and surgical antiadrenergic interventions, frequent use of sodium channel blockers, and implantable cardioverter–defibrillators (ICDs); however, the authors emphasize that therapy data remain insufficient for definitive recommendations. (crotti2023clinicalpresentationof pages 2-3)

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

6.1 2024 therapeutic innovation: antisense oligonucleotide (ASO) depletion strategy (proof-of-concept)

A 2024 Circulation study demonstrates a precision strategy that leverages the unusual redundancy that CALM1/2/3 encode identical protein: selectively depleting one affected gene can ameliorate phenotype while preserving total CaM protein. (bortolin2024antisenseoligonucleotidetherapy pages 1-3)

Key results:
- In human CALM1F142L/+ iPSC-derived cardiomyocytes, CALM1 knockout or CALM1-depleting ASOs normalized repolarization duration without altering overall CaM protein level. (bortolin2024antisenseoligonucleotidetherapy pages 1-3)
- In mice, an ASO targeting murine Calm1 reduced Calm1 transcript without reducing CaM protein, and alleviated drug-induced bidirectional ventricular tachycardia in Calm1N98S/+ animals without adverse cardiac electrical/contractile effects. (bortolin2024antisenseoligonucleotidetherapy pages 1-3)

While this work targeted CALM1 experimentally, the underlying principle is directly relevant to CALM3 because it depends on the three-gene/identical-protein architecture of human calmodulin. (bortolin2024antisenseoligonucleotidetherapy pages 1-3)

6.2 2023–2024 mechanistic consolidation

Recent 2023 reviews synthesize evidence that calmodulinopathic variants disproportionately disrupt Ca2+ binding in EF-hands and thereby perturb key pre-associated targets such as CaV1.2 (via CDI failure) and RyR2 (via altered inhibition), providing a molecular explanation for how heterozygous variants cause severe arrhythmias. (hussey2023calmodulinmutationsin pages 4-6, hussey2023calmodulinmutationsin pages 9-11)

7) Expert opinion and authoritative analysis (what experts emphasize)

Across the highest-authority clinical source (ICalmR) and mechanistic reviews, the convergent expert view is:
1) CALM variants cause severe, early-onset arrhythmia syndromes with high event rates, but phenotypic variability is broad and includes milder familial forms. (crotti2023clinicalpresentationof pages 2-3)
2) The C-lobe EF-hands (EF3/EF4) are a mechanistic hotspot, because impaired Ca2+ binding there undermines regulation of pre-associated targets (especially CaV1.2 CDI), producing dominant effects even when wild-type CaM is abundant. (hussey2023calmodulinmutationsin pages 9-11, crotti2023clinicalpresentationof pages 12-13)
3) Registries and systematic genetic screening are essential because of rarity, heterogeneity, and management uncertainty; improved outcomes over time likely reflect increased recognition and multi-modality care, but evidence remains insufficient for definitive, variant-specific treatment rules. (crotti2023clinicalpresentationof pages 2-3, crotti2023clinicalpresentationof pages 4-4)

8) Summary evidence map (table)

Topic	Key points	Quantitative data (if any)	Key sources (author year journal) and URLs
Identity	Verified target: human CALM3 encodes calmodulin-3, one of three human genes (CALM1/2/3) that encode the identical 149-aa calmodulin protein. CALM3 is a canonical calmodulin-family member, matching UniProt P0DP25 and the EF-hand calcium-sensor annotation. In heart, CALM3 transcript abundance is reported as relatively high among CALM genes, although newer expression analyses suggest gene contributions are tissue-dependent. (hussey2023calmodulinmutationsin pages 1-2, jensen2024calmodulinvariantsin pages 10-12)	149 aa protein; CALM genes on distinct chromosomes; CALM3 reported as highest relative abundance in human heart in one review. (hussey2023calmodulinmutationsin pages 1-2)	Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278; Jensen et al. 2024, medRxiv — https://doi.org/10.1101/2024.05.22.24307674
Structure	Calmodulin is a small, highly conserved Ca2+ sensor with two globular lobes (N and C) linked by a flexible central helix; each lobe contains two EF-hand motifs for a total of four Ca2+-binding sites. Ca2+ binding exposes hydrophobic surfaces that enable target engagement; methionine-rich surfaces contribute importantly to target recognition. (hussey2023calmodulinmutationsin pages 1-2, sobue2024calmodulinahighly pages 1-2, denesyuk2023canonicalstructuralbindingmodes pages 24-27)	N-lobe Kd ~16 µM and C-lobe Kd ~2.4 µM in one review; overall Ca2+ affinity reported in the ~5×10^-7 to 5×10^-6 M range; intracellular CaM concentration ~2–10 µM. (hussey2023calmodulinmutationsin pages 1-2, sobue2024calmodulinahighly pages 1-2)	Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278; Sobue 2024, Proc Jpn Acad Ser B — https://doi.org/10.2183/pjab.100.025; Denesyuk et al. 2023, J Biomol Struct Dyn — https://doi.org/10.1080/07391102.2022.2123391
Mechanism	CALM3/calmodulin is a signal transducer, not an enzyme: it binds Ca2+ and converts Ca2+ transients into conformational changes that regulate partner proteins. Many targets are pre-associated with apoCaM, and Ca2+ loading of one or both lobes triggers altered binding and target control. Disease mutations often preserve apo-binding but disrupt Ca2+-dependent switching. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 11-13, hussey2023calmodulinmutationsin pages 9-11)	Resting cytosolic Ca2+ ~10^-7 M; stimulated intracellular Ca2+ rises to 10^-6–10^-5 M; extracellular Ca2+ ~10^-3 M. (sobue2024calmodulinahighly pages 1-2)	Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278; Sobue 2024, Proc Jpn Acad Ser B — https://doi.org/10.2183/pjab.100.025
Pathways	Key pathways/targets include L-type Ca2+ channels (CaV1.2/CaV1.3), RyR2, SK channels, NaV1.5, CaMKII, and calcineurin/NFAT. Mechanistically, CaM mediates calcium-dependent inactivation/facilitation (CDI/CDF) of CaV channels, suppresses/reshapes RyR2 opening, enables SK gating, and activates CaMKII and calcineurin, linking it to excitation–contraction coupling, membrane excitability, transcriptional responses, and neuronal plasticity. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 9-11, hussey2023calmodulinmutationsin pages 13-15, hussey2023calmodulinmutationsin pages 4-6, sobue2024calmodulinahighly pages 6-19)	SK channels can bind 4 CaM molecules/channel; lobe-specific regulation documented for several channels. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 4-6)	Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278; Sobue 2024, Proc Jpn Acad Ser B — https://doi.org/10.2183/pjab.100.025
Localization	Calmodulin is ubiquitous and intracellular, functioning in the cytosol and on cytosolic faces of membrane proteins rather than as a secreted factor. It localizes functionally near plasma-membrane ion channels, intracellular Ca2+ release channels (e.g., RyR2, IP3R), and signaling complexes in heart, brain, immune cells, and muscle. CALM1-3 transcripts are also robustly expressed in brain cell types. (hussey2023calmodulinmutationsin pages 4-6, jensen2024calmodulinvariantsin pages 3-5, hussey2023calmodulinmutationsin pages 2-4, sobue2024calmodulinahighly pages 1-2)	Broad tissue distribution; mammalian intracellular CaM estimated at 2–10 µM. (sobue2024calmodulinahighly pages 1-2)	Sobue 2024, Proc Jpn Acad Ser B — https://doi.org/10.2183/pjab.100.025; Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278; Jensen et al. 2024, medRxiv — https://doi.org/10.1101/2024.05.22.24307674
Disease	Pathogenic variants in CALM1/2/3, including CALM3, cause calmodulinopathy, especially long QT syndrome (CALM-LQTS) and catecholaminergic polymorphic ventricular tachycardia (CALM-CPVT); variants cluster strongly in EF-hand/C-lobe regions that impair Ca2+ binding and downstream regulation of CaV1.2 and/or RyR2. Structural heart disease and neurological manifestations can also occur. (hussey2023calmodulinmutationsin pages 4-6, crotti2023clinicalpresentationof pages 10-11, crotti2023clinicalpresentationof pages 8-9, crotti2023clinicalpresentationof pages 12-13)	Registry: 140 subjects total; phenotypes LQTS 74 (53%), CPVT 36 (26%), LQTS/CPVT overlap 10 (7%), IVF 7 (5%), uncertain 11 (8%); structural cardiac abnormalities in 30%; symptomatic/arrhythmic event burden 74%; sudden death reduced from 27% in earlier cohort to 9% in updated cohort. Most P/LP variants (49/58, 84%) cluster in exons 5–6. (crotti2023clinicalpresentationof pages 3-4, crotti2023clinicalpresentationof pages 8-9, crotti2023clinicalpresentationof pages 2-3)	Crotti et al. 2023, European Heart Journal — https://doi.org/10.1093/eurheartj/ehad418; Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278
Applications	Current real-world implementation: CALM genes are now recognized as definitive arrhythmia genes and should be included in genetic testing/panel screening for LQTS/CPVT and in some genotype-negative arrest survivors. The International Calmodulinopathy Registry is a major clinical infrastructure for diagnosis, genotype–phenotype correlation, and management refinement. Standard care remains antiadrenergic therapy, sodium-channel blockers in some cases, and ICD/other interventions when needed. (crotti2023clinicalpresentationof pages 4-4, crotti2023clinicalpresentationof pages 2-3, hussey2023calmodulinmutationsin pages 17-18)	Registry nearly doubled from earlier reports to 140 enrolled subjects; 103 (74%) had cardiac events. (crotti2023clinicalpresentationof pages 4-4, crotti2023clinicalpresentationof pages 2-3)	Crotti et al. 2023, European Heart Journal — https://doi.org/10.1093/eurheartj/ehad418; Hussey et al. 2023, Channels — https://doi.org/10.1080/19336950.2023.2165278
Recent developments (2023–2024)	Major recent advances include: (1) expanded International Calmodulinopathy Registry showing broader phenotype spectrum and somewhat improved outcomes with modern management; (2) updated mechanistic syntheses linking variant effects to altered CaV1.2 CDI and RyR2 regulation; and (3) a 2024 antisense oligonucleotide (ASO) proof-of-concept showing that selective depletion of one mutant CALM gene can rescue cellular/animal phenotypes while preserving overall CaM protein through redundancy of the remaining CALM genes. (crotti2023clinicalpresentationof pages 3-4, bortolin2024antisenseoligonucleotidetherapy pages 1-3, bortolin2024antisenseoligonucleotidetherapy pages 3-5)	In 2024 ASO study, CALM1-targeting ASO reduced mutant-gene transcript, normalized repolarization in patient iPSC-cardiomyocytes, and alleviated bidirectional VT in mice without reducing total CaM protein. (bortolin2024antisenseoligonucleotidetherapy pages 1-3, bortolin2024antisenseoligonucleotidetherapy pages 3-5)	Bortolin et al. 2024, Circulation — https://doi.org/10.1161/circulationaha.123.068111; Crotti et al. 2023, European Heart Journal — https://doi.org/10.1093/eurheartj/ehad418
Data highlights	Recent human and experimental datasets support a C-lobe/EF-hand vulnerability model: disease-associated variants disproportionately affect the C-lobe and Ca2+-coordinating residues, with consequences for CaV1.2 and RyR2 regulation. Emerging neuropsychiatric work also suggests non-cardiac phenotypic expansion for some CALM variants, though cardiac calmodulinopathy remains the best-established disease context. (jensen2024calmodulinvariantsin pages 10-12, jensen2024calmodulinvariantsin pages 3-5, crotti2023clinicalpresentationof pages 12-13)	In a 2024 schizophrenia sequencing analysis, 7 CALM missense variants were found in cases vs 20 in controls, and all case variants mapped to the C-lobe; reported OR for carrying a C-lobe variant was 5.6. These findings are preliminary relative to established cardiac evidence. (jensen2024calmodulinvariantsin pages 10-12, jensen2024calmodulinvariantsin pages 3-5)	Jensen et al. 2024, medRxiv — https://doi.org/10.1101/2024.05.22.24307674; Crotti et al. 2023, European Heart Journal — https://doi.org/10.1093/eurheartj/ehad418

Table: This table summarizes verified identity, molecular function, pathways, localization, disease relevance, applications, and recent 2023-2024 developments for human CALM3/calmodulin. It is designed as a compact evidence map with quantitative findings and source URLs.

9) Practical functional annotation statement (for databases/curation)

CALM3 encodes calmodulin (CaM), a ubiquitous intracellular EF-hand Ca2+ sensor that binds four Ca2+ ions via two lobes (N and C) and regulates diverse target proteins through Ca2+-dependent conformational switching and frequent apoCaM pre-association. High-confidence regulated pathways include CaV1.2/CaV1.3 calcium-dependent inactivation/facilitation, RyR2 inhibition and Ca2+ release termination, SK channel gating, and Ca2+/CaM-dependent enzyme pathways (CaMKII, calcineurin/NFAT). Dominant missense variants—often in C-lobe EF-hands—cause calmodulinopathy (LQTS/CPVT) with high arrhythmic event rates; recent registry data quantify phenotype distributions and improving outcomes, and 2024 work provides proof-of-concept for gene-specific ASO depletion therapy exploiting redundancy across CALM genes. (hussey2023calmodulinmutationsin pages 2-4, hussey2023calmodulinmutationsin pages 9-11, hussey2023calmodulinmutationsin pages 4-6, crotti2023clinicalpresentationof pages 2-3, bortolin2024antisenseoligonucleotidetherapy pages 1-3)

10) Limitations of this report

The evidence set is strong for calmodulin’s molecular function and for clinical calmodulinopathy statistics (ICalmR), but does not include UniProt/GO text excerpts directly (the report relies on primary/review literature retrieved here).
Some emerging non-cardiac associations (e.g., schizophrenia) are from preprint literature and should be treated as provisional until peer-reviewed replication. (jensen2024calmodulinvariantsin pages 10-12)

References

(hussey2023calmodulinmutationsin pages 1-2): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(jensen2024calmodulinvariantsin pages 10-12): PhD Helene Halkjær Jensen, PhD Malene Brohus, BSc John W. Hussey III, Ana-Octavia Busuioc MSc, MSc Emil Drivsholm Iversen, MSc Faezeh Darki, MSc Gabriela Dobromirova Nikolova, MSc Amalie El-ton Baisgaard, PhD Palle Duun Rohde, Ida Elisabeth, M. D. Gad Holm, PhD Andrew McQuillin, PhD Tor-ben Moos, PhD Ivy E. Dick, PhD Michael Toft Overgaard, and M. Nyegaard. Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects. MedRxiv, May 2024. URL: https://doi.org/10.1101/2024.05.22.24307674, doi:10.1101/2024.05.22.24307674. This article has 2 citations.
(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 6 citations.
(denesyuk2023canonicalstructuralbindingmodes pages 24-27): Alexander I. Denesyuk, Sergei E. Permyakov, Eugene A. Permyakov, Mark S. Johnson, Konstantin Denessiouk, and Vladimir N. Uversky. Canonical structural-binding modes in the calmodulin–target protein complexes. Journal of Biomolecular Structure and Dynamics, 41:7582-7594, Sep 2023. URL: https://doi.org/10.1080/07391102.2022.2123391, doi:10.1080/07391102.2022.2123391. This article has 6 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 2-4): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 9-11): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 4-6): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(crotti2023clinicalpresentationof pages 8-9): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(crotti2023clinicalpresentationof pages 2-3): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(crotti2023clinicalpresentationof pages 3-4): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(crotti2023clinicalpresentationof pages 12-13): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(jensen2024calmodulinvariantsin pages 3-5): PhD Helene Halkjær Jensen, PhD Malene Brohus, BSc John W. Hussey III, Ana-Octavia Busuioc MSc, MSc Emil Drivsholm Iversen, MSc Faezeh Darki, MSc Gabriela Dobromirova Nikolova, MSc Amalie El-ton Baisgaard, PhD Palle Duun Rohde, Ida Elisabeth, M. D. Gad Holm, PhD Andrew McQuillin, PhD Tor-ben Moos, PhD Ivy E. Dick, PhD Michael Toft Overgaard, and M. Nyegaard. Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects. MedRxiv, May 2024. URL: https://doi.org/10.1101/2024.05.22.24307674, doi:10.1101/2024.05.22.24307674. This article has 2 citations.
(crotti2023clinicalpresentationof pages 4-4): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 1-3): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 11-13): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 13-15): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(sobue2024calmodulinahighly pages 6-19): 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 6 citations.
(crotti2023clinicalpresentationof pages 10-11): Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, and Peter J Schwartz. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. European Heart Journal, 44:3357-3370, Aug 2023. URL: https://doi.org/10.1093/eurheartj/ehad418, doi:10.1093/eurheartj/ehad418. This article has 66 citations and is from a highest quality peer-reviewed journal.
(hussey2023calmodulinmutationsin pages 17-18): John W. Hussey, Worawan B. Limpitikul, and Ivy E. Dick. Calmodulin mutations in human disease. Channels, Jan 2023. URL: https://doi.org/10.1080/19336950.2023.2165278, doi:10.1080/19336950.2023.2165278. This article has 54 citations and is from a peer-reviewed journal.
(bortolin2024antisenseoligonucleotidetherapy pages 3-5): Raul H. Bortolin, Farina Nawar, Chaehyoung Park, Michael A. Trembley, Maksymilian Prondzynski, Mason E. Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M. Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B. Cavazzoni, Peter T. Sage, Qing Ma, Robert D. Whitehill, Dominic J. Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A. Kubli, Adam E. Mullick, Vassilios J. Bezzerides, and William T. Pu. Antisense oligonucleotide therapy for calmodulinopathy. Circulation, 150:1199-1210, Oct 2024. URL: https://doi.org/10.1161/circulationaha.123.068111, doi:10.1161/circulationaha.123.068111. This article has 14 citations and is from a highest quality peer-reviewed journal.

Citations

hussey2023calmodulinmutationsin pages 1-2
denesyuk2023canonicalstructuralbindingmodes pages 24-27
sobue2024calmodulinahighly pages 1-2
hussey2023calmodulinmutationsin pages 2-4
hussey2023calmodulinmutationsin pages 9-11
hussey2023calmodulinmutationsin pages 4-6
crotti2023clinicalpresentationof pages 2-3
crotti2023clinicalpresentationof pages 3-4
crotti2023clinicalpresentationof pages 8-9
crotti2023clinicalpresentationof pages 12-13
crotti2023clinicalpresentationof pages 4-4
bortolin2024antisenseoligonucleotidetherapy pages 1-3
jensen2024calmodulinvariantsin pages 10-12
jensen2024calmodulinvariantsin pages 3-5
hussey2023calmodulinmutationsin pages 11-13
hussey2023calmodulinmutationsin pages 13-15
sobue2024calmodulinahighly pages 6-19
crotti2023clinicalpresentationof pages 10-11
hussey2023calmodulinmutationsin pages 17-18
bortolin2024antisenseoligonucleotidetherapy pages 3-5
https://doi.org/10.1080/19336950.2023.2165278;
https://doi.org/10.1101/2024.05.22.24307674
https://doi.org/10.2183/pjab.100.025;
https://doi.org/10.1080/07391102.2022.2123391
https://doi.org/10.2183/pjab.100.025
https://doi.org/10.1093/eurheartj/ehad418;
https://doi.org/10.1080/19336950.2023.2165278
https://doi.org/10.1161/circulationaha.123.068111;
https://doi.org/10.1093/eurheartj/ehad418
https://doi.org/10.1101/2024.05.22.24307674;
https://doi.org/10.1080/19336950.2023.2165278,
https://doi.org/10.1101/2024.05.22.24307674,
https://doi.org/10.2183/pjab.100.025,
https://doi.org/10.1080/07391102.2022.2123391,
https://doi.org/10.1093/eurheartj/ehad418,
https://doi.org/10.1161/circulationaha.123.068111,

📚 Additional Documentation

Notes

(CALM3-notes.md)

CALM3 notes

2026-03-19

Review scope: the CALM3 GOA file fetched on 2026-03-19 contains no literal ISO evidence-code rows, but it does contain multiple transferred annotations (IBA and IEA). I reviewed those in the spirit of [projects/ISO.md] by asking whether a term is safe to transfer across the human calmodulin paralogs.
Family identity: humans have three calmodulin genes, CALM1, CALM2, and CALM3, and all three encode an identical 149 aa calmodulin polypeptide PMID:27516456 PMID:31454269.
Family regulation differs even when protein sequence does not: transcription of the three genes is not equivalent, and in teratoma cells CALM3 was reported to be more highly transcribed than CALM1 or CALM2 PMID:9681195.
Curation consequence: core protein-level functions that follow directly from the conserved calmodulin sequence are safe to treat as family-wide, especially calcium binding, calcium sensing, kinase/phosphatase activation, and ion-channel regulation PMID:27516456 PMID:23040497.
Cardiac core function is strong for the protein family and directly relevant to CALM3: defective calmodulin regulation of RyR2 increases spontaneous calcium release events PMID:20226167 and the CALM3 A103V mutation promotes arrhythmogenic calcium waves and sparks PMID:27516456.
CALM3 also has direct human disease evidence for impaired L-type calcium channel regulation and action potential phenotypes in calmodulinopathy PMID:31454269.
Cell-division localization/function is supported independently of cardiac biology: calmodulin binds CP110 and loss of that interaction disrupts late cytokinesis PMID:16760425.
Microbial hijacking papers support genuine calmodulin biochemistry but not necessarily core host biological-process terms. OspC-family effectors bind calmodulin and block CaMKII / IFN signaling PMID:35568036, but those infection-context processes should stay non-core.
Several GOA terms are too context-specific to distinguish CALM3 from CALM1 / CALM2: synaptic localizations, myelin-associated terms, sperm terms, and specialized membrane-trafficking terms likely reflect cell-type context layered on top of the same calmodulin protein sequence rather than a CALM3-specific biochemical innovation PMID:9681195.
Some annotations should be removed or down-weighted on evidence quality grounds. substantia nigra development is based on proteomic detection in diseased tissue rather than developmental perturbation PMID:22926577.
Generic protein binding annotations are not informative for calmodulin and should not be favored when more specific regulator/binding terms are available.
Current UniProt entries for CALM1, CALM2, and CALM3 all show the same 149 aa sequence summary and I found no ALTERNATIVE PRODUCTS block in these local records, so there is no isoform-specific caveat comparable to the splice-isoform project genes [file:human/CALM1/CALM1-uniprot.txt "SQ SEQUENCE 149 AA"] [file:human/CALM2/CALM2-uniprot.txt "SQ SEQUENCE 149 AA"] [file:human/CALM3/CALM3-uniprot.txt "SQ SEQUENCE 149 AA"].

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

Moved out of the YAML description: annotations were interpreted at the protein level for this review because CALM1, CALM2, and CALM3 encode identical calmodulin proteins.

📄 View Raw YAML

id: P0DP25
gene_symbol: CALM3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CALM3 encodes one of the three human calmodulin genes and produces the same 149 amino acid
  calmodulin protein encoded by CALM1 and CALM2. The protein is a ubiquitous calcium sensor with four
  EF-hand motifs that binds calcium and regulates ion channels, protein kinases, protein phosphatases,
  and cell-division machinery. Because CALM1, CALM2, and CALM3 encode identical proteins, core
  calcium-sensing functions transfer well across the calmodulin family. Direct channel- and
  sarcoplasmic-reticulum calcium-release regulation can be retained as core even when assayed in
  cardiac cells, whereas broader cardiac electrophysiology or tissue-context terms reflect downstream
  physiology or recruitment rather than a CALM3-specific biochemical difference. CALM3 variants
  contribute to calmodulinopathy, including CPVT and long-QT phenotypes driven by dysregulated
  calcium-channel signaling.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
      supporting_text: CaM has two homologous globular domains (N- and C-lobes) connected by a flexible central helix; each lobe contains two canonical EF-hand helix-loop-helix motifs, yielding four Ca2+ binding sites per CaM molecule.
- 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
    supported_by:
    - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
      supporting_text: Calmodulin is a ubiquitously expressed Ca2+ sensor that transduces intracellular Ca2+ changes into functional regulation of diverse target proteins.
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Centrosomal localization for cell division
    action: 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: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:0002027
    label: regulation of heart rate
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Heart rate regulation through ion channel modulation
    action: ACCEPT
    reason: Retained as core because the annotation reflects direct calmodulin control of cardiac ion-channel and calcium-release machinery; broader downstream electrophysiology terms are kept non-core separately.
- term:
    id: GO:0005246
    label: calcium channel regulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulates L-type calcium channels and ryanodine receptors
    action: ACCEPT
    reason: Core calmodulin function or localization
    supported_by:
    - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
      supporting_text: CaM is pre-associated with CaV1.2, and C-lobe EF-hand mutations that reduce Ca2+ binding can blunt calcium-dependent inactivation, increasing Ca2+ entry and prolonging action potentials.
- 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:0005513
    label: detection of calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Core calcium sensing function
    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:0005876
    label: spindle microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Spindle microtubule association
    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:0000117
  review:
    summary: Activates adenylate cyclase for cAMP signaling
    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:0000117
  review:
    summary: Cardiac calcium-induced calcium release regulation
    action: ACCEPT
    reason: Retained as core because regulation of sequestered calcium release maps directly to calmodulin-RyR/SR calcium-release control, a core channel-regulatory mechanism despite the cardiac wording.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  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: IEA
  original_reference_id: GO_REF:0000117
  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: IEA
  original_reference_id: GO_REF:0000117
  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: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cytokinesis regulation with CP110 and centrin
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0034704
    label: calcium channel complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Component of calcium channel complexes
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Activates CaMKII and other calcium-dependent kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0060291
    label: long-term synaptic potentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Long-term synaptic potentiation reflects specialized neuronal signaling.
    action: KEEP_AS_NON_CORE
    reason: Calmodulin is important for synaptic plasticity, but this is a tissue-specific
      downstream context and should not be used to distinguish CALM3 from CALM1 or
      CALM2.
- term:
    id: GO:0072542
    label: protein phosphatase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Activates calcineurin (PP2B) phosphatase
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:1901844
    label: regulation of cell communication by electrical coupling involved in cardiac
      conduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cardiac electrical coupling regulation
    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:35271311
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- 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: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:0008076
    label: voltage-gated potassium channel complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: KCNQ channel complex component
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: General membrane localization is plausible but not a core assignment.
    action: KEEP_AS_NON_CORE
    reason: Calmodulin is recruited to membrane-associated channels and receptors,
      but broad membrane localization is secondary to its core soluble calcium-sensor
      role.
- 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: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: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:0031982
    label: vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Vesicle association is observed in specialized trafficking or exosome
      contexts.
    action: KEEP_AS_NON_CORE
    reason: Vesicle localization reflects specific cell-type and trafficking contexts
      rather than a defining family-wide localization for the identical calmodulin
      protein.
- 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: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:0044305
    label: calyx of Held
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Calyx of Held synapse localization
    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: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:0097225
    label: sperm midpiece
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Sperm midpiece localization
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- 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: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:0140238
    label: presynaptic endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Presynaptic vesicle endocytosis
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0141110
    label: transporter inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This term is too specific for the available transfer evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Calmodulin modulates multiple transporters and channels, but a generic
      transporter inhibitor term overstates a context-dependent regulatory effect.
- 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:1905913
    label: negative regulation of calcium ion export across plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of calcium export is plausible in channel-regulatory
      contexts but not a core assignment.
    action: KEEP_AS_NON_CORE
    reason: This term reflects a specific downstream physiological setting of calmodulin-dependent
      channel regulation rather than a defining family-wide process.
- 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:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9956602
  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-HSA-9956624
  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-HSA-9956667
  review:
    summary: Soluble cytosolic protein
    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: IDA
  original_reference_id: PMID:23040497
  review:
    summary: Cardiac calcium-induced calcium release regulation
    action: ACCEPT
    reason: Retained as core because PMID:23040497 directly supports calmodulin regulation of RyR-mediated sarcoplasmic-reticulum calcium release; broader cardiac electrophysiology phenotypes are treated as non-core.
- term:
    id: GO:1901844
    label: regulation of cell communication by electrical coupling involved in cardiac
      conduction
  evidence_type: IDA
  original_reference_id: PMID:23040497
  review:
    summary: Cardiac electrical coupling regulation
    action: KEEP_AS_NON_CORE
    reason: Kept non-core because cardiac electrical coupling is a downstream tissue-level conduction phenotype rather than the direct calmodulin biochemical mechanism, which is captured by calcium/channel regulatory terms.
- term:
    id: GO:0005246
    label: calcium channel regulator activity
  evidence_type: IDA
  original_reference_id: PMID:20226167
  review:
    summary: Regulates L-type calcium channels and ryanodine receptors
    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: IDA
  original_reference_id: PMID:20226167
  review:
    summary: Cardiac calcium-induced calcium release regulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0060291
    label: long-term synaptic potentiation
  evidence_type: TAS
  original_reference_id: PMID:20668654
  review:
    summary: Long-term synaptic potentiation reflects specialized neuronal signaling.
    action: KEEP_AS_NON_CORE
    reason: Calmodulin is important for synaptic plasticity, but this is a tissue-specific
      downstream context and should not be used to distinguish CALM3 from CALM1 or
      CALM2.
- term:
    id: GO:0097720
    label: calcineurin-mediated signaling
  evidence_type: IDA
  original_reference_id: PMID:8631777
  review:
    summary: Activates calcineurin phosphatase for NFAT signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11984006
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19855925
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:35568036
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: IDA
  original_reference_id: PMID:35568036
  review:
    summary: Activates CaMKII and other calcium-dependent kinases
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:31454269
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0098901
    label: regulation of cardiac muscle cell action potential
  evidence_type: IMP
  original_reference_id: PMID:31454269
  review:
    summary: Cardiac action potential regulation
    action: KEEP_AS_NON_CORE
    reason: Kept non-core because action-potential regulation is a cardiac electrophysiology endpoint downstream of calmodulin control of CaV/RyR channels, not a distinct core molecular function.
- term:
    id: GO:1901842
    label: negative regulation of high voltage-gated calcium channel activity
  evidence_type: IMP
  original_reference_id: PMID:31454269
  review:
    summary: Calcium channel activity regulation
    action: ACCEPT
    reason: Accepted as direct channel regulation because PMID:31454269 supports impaired calcium-dependent inactivation of L-type calcium channels by calmodulin variants; this is closer to the core mechanism than the downstream action-potential phenotype.
- term:
    id: GO:0010856
    label: adenylate cyclase activator activity
  evidence_type: IDA
  original_reference_id: PMID:11807546
  review:
    summary: Activates adenylate cyclase for cAMP signaling
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0034704
    label: calcium channel complex
  evidence_type: IDA
  original_reference_id: PMID:23040497
  review:
    summary: Component of calcium channel complexes
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: IDA
  original_reference_id: PMID:16760425
  review:
    summary: Spindle pole localization during mitosis
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10692436
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15140941
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15632291
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16760425
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21299499
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:3111527
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  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: TAS
  original_reference_id: PMID:10899953
  review:
    summary: Primary cytoplasmic localization
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:16760425
  review:
    summary: Centrosomal localization for cell division
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005876
    label: spindle microtubule
  evidence_type: IDA
  original_reference_id: PMID:16760425
  review:
    summary: Spindle microtubule association
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:10899953
  review:
    summary: Plasma membrane association occurs in specific signaling contexts.
    action: KEEP_AS_NON_CORE
    reason: Calmodulin can associate with membrane-proximal receptor and channel complexes,
      but plasma membrane residence is context dependent rather than a defining family-wide
      localization.
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:10899953
  review:
    summary: Calmodulin modulates selected GPCR signaling pathways in specialized
      contexts.
    action: KEEP_AS_NON_CORE
    reason: This captures a real signaling interaction, but the evidence is receptor-
      and context-specific and should not be treated as a defining CALM3 function
      relative to the other calmodulin paralogs.
- term:
    id: GO:0021762
    label: substantia nigra development
  evidence_type: HEP
  original_reference_id: PMID:22926577
  review:
    summary: Proteomic detection in substantia nigra does not justify a developmental
      annotation.
    action: REMOVE
    reason: The cited evidence is expression/proteomics in diseased tissue, not functional
      evidence for substantia nigra development.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: HDA
  original_reference_id: PMID:19190083
  review:
    summary: Vesicle association is observed in specialized trafficking or exosome
      contexts.
    action: KEEP_AS_NON_CORE
    reason: Vesicle localization reflects specific cell-type and trafficking contexts
      rather than a defining family-wide localization for the identical calmodulin
      protein.
- term:
    id: GO:0032465
    label: regulation of cytokinesis
  evidence_type: IMP
  original_reference_id: PMID:16760425
  review:
    summary: Cytokinesis regulation with CP110 and centrin
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:11807546
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0008179
    label: adenylate cyclase binding
  evidence_type: IPI
  original_reference_id: PMID:11807546
  review:
    summary: Direct adenylate cyclase binding is supported, but mainly in host-pathogen
      interaction studies.
    action: KEEP_AS_NON_CORE
    reason: The interaction is real biochemistry for calmodulin, but the cited evidence
      centers on bacterial edema-factor activation rather than a defining endogenous
      CALM3 role.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19855925
  review:
    summary: Too general - more specific terms available
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general - more specific terms are available
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: IDA
  original_reference_id: PMID:11807546
  review:
    summary: Part of enzyme complexes
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0002027
    label: regulation of heart rate
  evidence_type: IMP
  original_reference_id: PMID:23040497
  review:
    summary: Heart rate regulation through ion channel modulation
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:23040497
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:7607248
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:8631777
  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: IMP
  original_reference_id: PMID:23040497
  review:
    summary: Core calcium sensing function
    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: IDA
  original_reference_id: PMID:20226167
  review:
    summary: Regulates RyR-mediated calcium release from SR
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:20668654
  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: IDA
  original_reference_id: PMID:20226167
  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: IPI
  original_reference_id: PMID:7607248
  review:
    summary: Titin binding in muscle
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific or specialized function
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: TAS
  original_reference_id: PMID:20668654
  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: IPI
  original_reference_id: PMID:21167176
  review:
    summary: Binds ion channels and transporters
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IPI
  original_reference_id: PMID:23040497
  review:
    summary: Binds ion channels and transporters
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:7607248
  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: IMP
  original_reference_id: PMID:23040497
  review:
    summary: Cardiac contraction through calcium channel regulation
    action: ACCEPT
    reason: Retained as core because the evidence links calmodulin to cardiac contraction through direct RyR/calcium-channel regulation; broader tissue-level electrical-conduction phenotypes remain non-core.
- term:
    id: GO:0072542
    label: protein phosphatase activator activity
  evidence_type: IDA
  original_reference_id: PMID:8631777
  review:
    summary: Activates calcineurin (PP2B) phosphatase
    action: ACCEPT
    reason: Core calmodulin function or localization
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:27516456
  review:
    summary: Core calcium-binding function through 4 EF-hand domains
    action: ACCEPT
    reason: Core calmodulin function or localization
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF: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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10692436
  title: Ca(2+)-dependent and Ca(2+)-independent calmodulin binding sites in erythrocyte
    protein 4.1. Implications for regulation of protein 4.1 interactions with transmembrane
    proteins.
  findings: []
- id: PMID:10899953
  title: Calmodulin regulation of basal and agonist-stimulated G protein coupling
    by the mu-opioid receptor (OP(3)) in morphine-pretreated cell.
  findings: []
- id: PMID:11807546
  title: Structural basis for the activation of anthrax adenylyl cyclase exotoxin
    by calmodulin.
  findings: []
- id: PMID:11984006
  title: The Chediak-Higashi protein interacts with SNARE complex and signal transduction
    proteins.
  findings: []
- id: PMID:15140941
  title: Ca2+-binding protein-1 facilitates and forms a postsynaptic complex with
    Cav1.2 (L-type) Ca2+ channels.
  findings: []
- id: PMID:15632291
  title: Myristoyl moiety of HIV Nef is involved in regulation of the interaction
    with calmodulin in vivo.
  findings: []
- id: PMID:16760425
  title: CP110 cooperates with two calcium-binding proteins to regulate cytokinesis
    and genome stability.
  findings: []
- id: PMID:19190083
  title: 'Characterization of exosome-like vesicles released from human tracheobronchial
    ciliated epithelium: a possible role in innate defense.'
  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:20226167
  title: Defective calmodulin binding to the cardiac ryanodine receptor plays a key
    role in CPVT-associated channel dysfunction.
  findings: []
- id: PMID:20668654
  title: Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism
    of CaMKII kinase activation.
  findings: []
- id: PMID:21167176
  title: Solution NMR structure of Apo-calmodulin in complex with the IQ motif of
    human cardiac sodium channel NaV1.5.
  findings: []
- id: PMID:21299499
  title: 'IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and
    myosin essential light chain.'
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:22926577
  title: Quantitative proteomic analysis of human substantia nigra in Alzheimer's
    disease, Huntington's disease and Multiple sclerosis.
  findings: []
- id: PMID:23040497
  title: Mutations in calmodulin cause ventricular tachycardia and sudden cardiac
    death.
  findings: []
- id: PMID:27516456
  title: Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates
    Arrhythmogenic Ca Waves and Sparks.
  findings: []
- id: PMID:3111527
  title: 'Comparison of S100b protein with calmodulin: interactions with melittin
    and microtubule-associated tau proteins and inhibition of phosphorylation of tau
    proteins by protein kinase C.'
  findings: []
- id: PMID:31454269
  title: Genetic Mosaicism in Calmodulinopathy.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:35568036
  title: A family of conserved bacterial virulence factors dampens interferon responses
    by blocking calcium signaling.
  findings: []
- id: PMID:7607248
  title: A calmodulin-binding sequence in the C-terminus of human cardiac titin kinase.
  findings: []
- id: PMID:8631777
  title: Blocking the Ca2+-induced conformational transitions in calmodulin with disulfide
    bonds.
  findings: []
- id: Reactome:R-HSA-9956602
  title: CALM binds bacterial OspC3
  findings: []
- id: Reactome:R-HSA-9956624
  title: OspC3 ADP-riboxanates CASP4
  findings: []
- id: Reactome:R-HSA-9956667
  title: CASP4 binds CALM:OspC3
  findings: []
- id: PMID:9681195
  title: Characterization of the human CALM2 calmodulin gene and comparison of the
    transcriptional activity of CALM1, CALM2 and CALM3.
  findings: []
- id: file:human/CALM3/CALM3-notes.md
  title: Curator notes for CALM3 review
  findings: []
- id: file:human/CALM3/CALM3-deep-research-falcon.md
  title: Falcon deep research report for CALM3
  findings:
  - statement: Falcon research supports CALM3 as one of three human genes encoding identical calmodulin, a four-EF-hand calcium sensor that regulates target proteins including CaMKII, calcineurin, voltage-gated calcium channels, and ryanodine receptors.
    supporting_text: three distinct human genes (CALM1, CALM2, CALM3) encode identical 149-aa calmodulin (CaM) protein sequences
core_functions:
- description: Primary intracellular calcium sensor. CALM3-encoded calmodulin binds
    calcium through four EF-hand motifs and converts calcium fluctuations into target-protein
    regulation.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  directly_involved_in:
  - id: GO:0005513
    label: detection of calcium ion
  supported_by:
  - reference_id: PMID:27516456
    supporting_text: Humans have 3 CaM genes ( CALM1 , CALM2 , and CALM3 ) encoding
      for a perfectly conserved sequence of amino acids
  - reference_id: PMID:23040497
    supporting_text: Both CALM1 substitutions demonstrated compromised calcium binding
  - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
    supporting_text: CaM has two homologous globular domains (N- and C-lobes) connected by a flexible central helix; each lobe contains two canonical EF-hand helix-loop-helix motifs, yielding four Ca2+ binding sites per CaM molecule.
- description: Core calcium-dependent signal-transduction adaptor for kinase and phosphatase
    regulation, especially CaMK and calcineurin pathways.
  molecular_function:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  directly_involved_in:
  - id: GO:0097720
    label: calcineurin-mediated signaling
  supported_by:
  - reference_id: PMID:20668654
    supporting_text: Structure of the CaMKIIdelta/calmodulin complex reveals the molecular
      mechanism of CaMKII kinase activation.
  - reference_id: PMID:35568036
    supporting_text: IFN inhibition was mediated by the binding of OspC1 and OspC3
      to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II
  - reference_id: PMID:8631777
    supporting_text: Blocking the Ca2+-induced conformational transitions in calmodulin
      with disulfide bonds.
  - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
    supporting_text: Ca2+/CaM activates CaMKII and calcineurin, linking CaM to phosphorylation/dephosphorylation cascades.
- description: Regulator of cardiac and other excitable-cell calcium channels, especially
    RyR2 and high-voltage-gated calcium-channel pathways.
  molecular_function:
    id: GO:0005246
    label: calcium channel regulator activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  directly_involved_in:
  - id: GO:0010880
    label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic
      reticulum
  supported_by:
  - reference_id: PMID:20226167
    supporting_text: the addition of a high concentration of CaM attenuated the aberrant
      increase of Ca(2+) sparks
  - reference_id: PMID:27516456
    supporting_text: A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark
      activity
  - reference_id: PMID:31454269
    supporting_text: Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing
      mutant or wild-type CaM showed that both mutants impaired Ca2+-dependent inactivation
      of L-type Ca2+ channels and prolonged action potential duration
  - reference_id: file:human/CALM3/CALM3-deep-research-falcon.md
    supporting_text: CaM regulates intracellular Ca2+ release channels. Notably, RyR2 is inhibited by both apoCaM and Ca2+/CaM.
- description: Centrosome-associated regulator of late cytokinesis through CP110/centrin-containing
    cell-division machinery.
  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
  supported_by:
  - reference_id: PMID:16760425
    supporting_text: its depletion leads to a failure at a late stage of cytokinesis
      and the formation of binucleate cells

CALM3

Gene Description

Existing Annotations Review

Core Functions

Primary intracellular calcium sensor. CALM3-encoded calmodulin binds calcium through four EF-hand motifs and converts calcium fluctuations into target-protein regulation.

Core calcium-dependent signal-transduction adaptor for kinase and phosphatase regulation, especially CaMK and calcineurin pathways.

Regulator of cardiac and other excitable-cell calcium channels, especially RyR2 and high-voltage-gated calcium-channel pathways.

Centrosome-associated regulator of late cytokinesis through CP110/centrin-containing cell-division machinery.

References

Deep Research

Falcon

Research report: Human CALM3 (UniProt P0DP25) — functional annotation, pathways, and clinical relevance

0) Verification of correct gene/protein identity (critical)

1) Key concepts and definitions (current understanding)

1.1 What CALM3 encodes: a Ca2+ sensor (not an enzyme)

1.2 Core structural definition: EF-hands and two lobes

1.3 Calcium-binding mechanism and Ca2+-triggered switching

1.4 Quantitative Ca2+ binding properties (biophysical “definition” of lobe asymmetry)

2) Primary biological function, pathways, and mechanisms of action

2.1 Primary function: regulate targets by apoCaM pre-association and Ca2+-dependent switching

2.2 Canonical and high-confidence pathways/targets relevant to functional annotation

3) Subcellular localization: where CALM3’s protein product acts

4) Disease relevance of CALM3: calmodulinopathy and variant mechanisms

4.1 Disease entity and phenotypes

4.2 Variant clustering and molecular interpretation

4.3 Extra-cardiac manifestations (interpretation and caution)

5) Current applications and real-world implementations

5.1 Diagnostic implementation: genetic testing and registry-guided practice

5.2 Management approaches documented in contemporary cohorts

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

6.1 2024 therapeutic innovation: antisense oligonucleotide (ASO) depletion strategy (proof-of-concept)

6.2 2023–2024 mechanistic consolidation

7) Expert opinion and authoritative analysis (what experts emphasize)

8) Summary evidence map (table)

9) Practical functional annotation statement (for databases/curation)

10) Limitations of this report

Citations

📚 Additional Documentation

Notes

CALM3 notes

2026-03-19

Description cleanup note

📄 View Raw YAML