Affinage

CALM1

Calmodulin-1 · UniProt P0DP23

Round 2 corrected
Length
149 aa
Mass
16.8 kDa
Annotated
2026-04-28
74 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CALM1 encodes calmodulin-1, one of three genes producing the identical 149-residue Ca²⁺-sensing protein calmodulin, which transduces intracellular calcium signals by undergoing a conformational change—unwinding its central helix to form a hydrophobic tunnel that engulfs target peptides—thereby activating or inhibiting diverse effectors including smooth muscle MLCK, SK potassium channels (gated by N-lobe Ca²⁺ binding), eNOS (regulated by PKC-mediated Thr495 phosphorylation), and NMDA receptors (where Ca²⁺/CaM binding to NR1 reduces channel open probability ~4-fold) (PMID:1519061, PMID:8625412, PMID:11323678, PMID:11397791). CALM1 contributes approximately 45% of total cardiac calmodulin protein and is the dominant translational source alongside CALM2; missense mutations (e.g., F142L, N98S, F90L) that reduce Ca²⁺ affinity cause dominant impairment of Ca²⁺-dependent inactivation of the cardiac L-type calcium channel CaV1.2, producing long QT syndrome and catecholaminergic ventricular arrhythmias exacerbated by β-adrenergic stimulation (PMID:41846582, PMID:32929985, PMID:28158429, PMID:26969752). Beyond the heart, CALM1 has gene-specific roles in precerebellar neuron migration not compensated by CALM2/3, and its axonal translation is locally controlled by an FMRP/miR-181d repression complex that is relieved by NGF to promote axon elongation (PMID:25519244, PMID:26711345). A de novo CALM1 variant (p.E140V) causes a neurological phenotype (hypotonia, intellectual disability) without cardiac arrhythmia, through aberrant splicing producing C-terminally truncated calmodulin, establishing genotype-specific mechanisms for cardiac versus neurological calmodulinopathy (PMID:41467504).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1992 High

    The structural basis of calmodulin target recognition was established: Ca²⁺-bound CaM unwinds its central helix and wraps both lobes around a helical target peptide in a hydrophobic tunnel, explaining how a single sensor activates structurally diverse targets.

    Evidence 2.4 Å X-ray crystal structure of Ca²⁺/CaM–MLCK peptide complex

    PMID:1519061

    Open questions at the time
    • Structure captured a single target peptide; the mechanism of selectivity among hundreds of CaM targets was not resolved
    • Dynamics of the central helix unwinding in solution remained unknown
  2. 1993 High

    Genomic organization of the three human calmodulin genes was defined, mapping CALM1 to 14q24–q31 and showing that all three genes encode identical protein yet are dispersed across different chromosomes, raising the question of why three genes are maintained.

    Evidence PCR from somatic cell hybrids plus chromosomal in situ hybridization; Northern blot and promoter analysis of CALM1 gene structure

    PMID:7925473 PMID:8314583

    Open questions at the time
    • Relative protein contributions of each CALM gene to total calmodulin were unknown
    • Functional redundancy versus gene-specific requirements not tested
  3. 1996 High

    CaM was identified as a direct Ca²⁺-dependent negative regulator of NMDA receptors, binding the NR1 subunit to reduce channel open probability ~4-fold and competing with the cytoskeletal anchor α-actinin-2 for the same NR1 binding site, establishing a feedback mechanism linking Ca²⁺ influx to receptor inactivation and cytoskeletal detachment.

    Evidence Patch-clamp electrophysiology of NR1/NR2 channels; co-immunoprecipitation from brain; in vitro competition binding with α-actinin-2

    PMID:8625412 PMID:9009191

    Open questions at the time
    • In vivo significance of CaM–NR1 feedback for synaptic plasticity not demonstrated
    • Whether CALM1-specific mRNA regulation affects this process was unknown
  4. 1997 High

    CaM was shown to function as a constitutive, integral subunit of SK channels, with Ca²⁺ binding exclusively to the N-lobe EF hands triggering channel gating—the first demonstration that CaM acts as a permanent channel subunit rather than a transient activator.

    Evidence Biochemical binding assays; 1.60 Å crystal structure of CaMBD–Ca²⁺–CaM complex (2001)

    PMID:11323678

    Open questions at the time
    • Whether CaM lobe-specificity generalizes to other channel targets was unclear
    • Isoform-specific contributions of CALM1/2/3 to SK channel CaM pools not addressed
  5. 2001 High

    The molecular switch controlling Ca²⁺/CaM-dependent eNOS activation was identified: constitutive PKC phosphorylation of Thr495 blocks CaM binding, while agonist-induced PP1 dephosphorylation permits CaM association and enzyme activation.

    Evidence Site-directed mutagenesis of Thr495, co-immunoprecipitation, pharmacological inhibition in porcine aortic endothelial cells

    PMID:11397791

    Open questions at the time
    • Structural basis of how pThr495 sterically blocks CaM binding was not resolved
    • In vivo vascular consequences of Thr495 variants not tested
  6. 2013 Medium

    The first causative link between a CALM1 missense mutation (F90L) and a life-threatening cardiac arrhythmia (idiopathic ventricular fibrillation) was established, demonstrating that even heterozygous disruption of CaM–target interactions is pathogenic.

    Evidence Exome sequencing and pedigree analysis of affected family

    PMID:24076290

    Open questions at the time
    • No functional reconstitution of F90L effect on specific ion channels in this study
    • Dominant-negative versus haploinsufficiency mechanism not distinguished
  7. 2015 Medium

    Axonal CALM1 mRNA translation was shown to be locally regulated by an FMRP/miR-181d repressive complex; NGF relieves this repression, promoting local calmodulin synthesis and axon elongation—establishing a gene-specific post-transcriptional mechanism for CALM1 in neural development.

    Evidence Co-IP of FMRP with miR-181d/Calm1 mRNA; Fmr1 KO and miR-181d overexpression; axonal fractionation in primary sensory neurons

    PMID:26711345

    Open questions at the time
    • Whether CALM2/3 mRNAs are similarly regulated by FMRP/miRNAs was not tested
    • In vivo relevance for axon guidance phenotypes not demonstrated
  8. 2016 High

    The convergent arrhythmia mechanism of calmodulinopathy variants was defined: reduced Ca²⁺ affinity of mutant CaM causes dominant loss of Ca²⁺-dependent inactivation (CDI) of CaV1.2, with the E141G variant showing 11-fold reduced Ca²⁺ binding—while RyR2 function and NaV1.5 were only mildly affected, pinpointing CaV1.2 CDI as the primary arrhythmogenic target.

    Evidence Ca²⁺ binding affinity measurements; patch-clamp of CaV1.2, NaV1.5; RyR2 Ca²⁺ release assays in heterologous cells; patient iPSC-CM electrophysiology with verapamil rescue

    PMID:26969752 PMID:28158429

    Open questions at the time
    • How a single mutant allele among six CALM alleles achieves dominant-negative effect on the CaV1.2 macromolecular complex was incompletely explained
    • Long-term remodeling effects in intact hearts not captured
  9. 2020 High

    A CRISPR knock-in mouse model (Calm1-N98S) demonstrated that β-adrenergic stimulation is the critical trigger for arrhythmogenesis: isoproterenol exacerbated ICaL density, slowed inactivation, and provoked both reentrant and focal arrhythmias (EADs, DADs), providing the first in vivo mechanistic model of calmodulinopathic LQTS.

    Evidence CRISPR/Cas9 heterozygous knock-in mice (two independent lines); ECG; optical voltage mapping; patch-clamp; Ca²⁺ imaging; His-Purkinje microelectrode recording

    PMID:32929985

    Open questions at the time
    • Whether β-blocker therapy is sufficient to prevent sudden death long-term was not established
    • Tissue-specific contributions of CALM1 versus CALM2/3 in the mouse heart not quantified in this study
  10. 2024 Medium

    A SupRep gene therapy strategy—simultaneously knocking down all three CALM genes with shRNAs and replacing with shRNA-immune CALM1 cDNA—rescued prolonged APD in patient iPSC-CMs carrying mutations in any of the three CALM genes, establishing a unified therapeutic approach for calmodulinopathies.

    Evidence Lentiviral SupRep construct in iPSC-CMs from CALM1-F142L, CALM2-D130G, CALM3-D130G patients; voltage-sensing dye APD90 measurement

    PMID:39069900

    Open questions at the time
    • In vivo delivery, long-term expression, and cardiac-specific targeting not demonstrated
    • Potential off-target effects of triple CALM knockdown on non-cardiac tissues not assessed
  11. 2025 Medium

    Ribosome profiling of human heart resolved the long-standing question of paralog contributions: CALM1 and CALM2 each supply ~45% of cardiac calmodulin protein while CALM3 contributes ~11%, explaining the greater clinical severity and stronger purifying selection on CALM1 variants.

    Evidence Ribosome profiling of left ventricle (GTEx); RNA-seq from 49 tissues; gnomAD constraint analysis; International Calmodulinopathy Registry

    PMID:41846582

    Open questions at the time
    • Whether translational efficiency varies across cardiac cell types (atrial vs. ventricular vs. conduction system) is unknown
    • Developmental dynamics of CALM paralog translation not assessed
  12. 2026 Medium

    A neurological calmodulinopathy phenotype distinct from cardiac arrhythmia was attributed to a CALM1 variant (E140V) that predominantly generates aberrantly spliced, C-terminally truncated calmodulin rather than the missense protein—establishing that the molecular mechanism (splice disruption vs. Ca²⁺ affinity loss) determines tissue-specific disease outcome.

    Evidence RNA-seq of patient blood showing splice donor gain/intron retention; C. elegans cmd-1 modeling comparing E140V vs. E141G phenotypes

    PMID:41467504

    Open questions at the time
    • Brain-specific expression of truncated calmodulin not directly confirmed (blood RNA-seq used)
    • How truncated CaM produces hypotonia and intellectual disability at the molecular level is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how a single mutant CaM allele among six achieves dominant-negative effects on specific channel complexes in vivo, (2) the structural basis of CALM1 gene-specific functions in neuronal migration and axonal translation that are not compensated by CALM2/3, and (3) the physiological significance of CaM as a structural subunit of the UBR4 E4 ubiquitin ligase complex for substrate selection and protein homeostasis.
  • Dominant-negative mechanism at the level of CaM–CaV1.2 stoichiometry not quantitatively modeled in vivo
  • CALM1-specific neuronal functions may reflect 3'UTR/5'UTR-mediated mRNA regulation rather than protein-level differences, but this has not been directly tested
  • UBR4–KCMF1–CaM complex function awaits peer-reviewed validation and identification of endogenous substrates

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0140299 molecular sensor activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1 R-HSA-392499 Metabolism of proteins 1
Partners
ACTN2CACNA1CFMRPGRIN1KCMF1KCNN2NOS3UBR4
Complex memberships
SK channel complexUBR4–KCMF1–CaM E4 ligase complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Crystal structure of Ca2+-bound calmodulin complexed with a peptide analog of the smooth muscle myosin light chain kinase (MLCK) CaM-binding region at 2.4 Å resolution revealed that CaM forms a compact ellipsoidal tunnel that engulfs the helical target peptide; the central helix of CaM unwinds and expands into a bend between residues 73–77, allowing both hydrophobic domains to merge into a single area surrounding the peptide, with ~185 contacts formed. This established the structural basis of CaM target-peptide recognition. X-ray crystallography (2.4 Å resolution) of Ca2+/CaM–MLCK peptide complex Science High 1519061
1996 Ca2+-dependent binding of calmodulin to the NR1 subunit of NMDA receptors causes a ~4-fold reduction in NMDA channel open probability, establishing CaM as a direct negative regulator of NMDA receptor activity through a Ca2+-dependent feedback mechanism. Protein purification, in vitro binding assay, co-immunoprecipitation from brain, patch-clamp electrophysiology of homomeric NR1 and heteromeric NR1/NR2 complexes Cell High 8625412
1997 Calmodulin binds to the CaM-binding domain of SK (small-conductance Ca2+-activated K+) channel α-subunits constitutively; upon Ca2+ binding exclusively to the N-lobe EF hands of CaM, channel opening is triggered. The interaction is obligatory for channel gating, placing CaM as an intrinsic subunit of SK channels. Biochemical binding assays; later (2001) crystal structure at 1.60 Å of CaMBD/Ca2+/CaM showing CaM wrapping around three α-helices from a dimeric CaMBD Nature (structure paper 2001) High 11323678
1997 α-Actinin-2 and calmodulin compete for binding to the cytoplasmic tail of the NR1 subunit of NMDA receptors in a Ca2+-dependent manner: Ca2+/calmodulin directly antagonizes NR1–α-actinin binding, suggesting a mechanism by which Ca2+ entry through NMDA receptors can displace cytoskeletal anchoring and regulate receptor localization and activity. Yeast two-hybrid, co-immunoprecipitation from rat brain, in vitro competition binding assay Nature High 9009191
1997 Genetically encoded FRET-based Ca2+ indicators ('cameleons') were constructed using tandem fusions of cyan-GFP, calmodulin, the CaM-binding peptide M13, and yellow-GFP. Ca2+ binding causes CaM to wrap around M13, increasing FRET between flanking GFPs, enabling real-time measurement of free Ca2+ in cytosol, nucleus, and ER of live cells. CaM mutations were used to tune Ca2+ affinity over the range 10⁻⁸–10⁻² M. Genetic engineering, FRET imaging in live HeLa cells, calmodulin mutagenesis Nature High 9278050
2001 Calmodulin binding to the CaM-binding domain of eNOS is regulated by phosphorylation: constitutive phosphorylation of Thr495 (by PKC) reduces CaM binding, while agonist-induced dephosphorylation of Thr495 by PP1 promotes CaM association and enhances eNOS activity. Mutation of Thr495 to Ala increased CaM binding in unstimulated cells, while Asp495 abolished CaM binding, confirming phosphorylation as the molecular switch controlling Ca2+/CaM-dependent eNOS activation. Co-immunoprecipitation, site-directed mutagenesis, CaM binding assay, pharmacological inhibitors (Ro 31-8220, calyculin A, KN-93) in porcine aortic endothelial cells Circulation Research High 11397791
1993 Chromosomal localization of the three bona fide human calmodulin genes: CALM1 maps to chromosome 14q24–q31, CALM2 to 2p21.1–p21.3, and CALM3 to 19q13.2–q13.3, establishing that these identical-protein-encoding genes are dispersed throughout the genome. PCR-based amplification from human-hamster somatic cell hybrids; in situ hybridization on human lymphocyte metaphase spreads Genomics High 8314583
1994 The human CALM1 gene contains six exons spanning ~10 kb of genomic DNA with a cluster of transcription-start sites 200 bp upstream of the ATG codon. Expression is ubiquitous but differential: a 1.7 kb mRNA is uniformly present while a 4.2 kb mRNA is enriched in brain and skeletal muscle. Two intronless, non-functional pseudogenes (CALM1P1, CALM1P2) were characterized. Genomic library screening, PCR, Northern blotting, sequencing of human CALM1 gene and flanking regions European Journal of Biochemistry High 7925473
1998 Comparison of transcriptional activity of CALM1, CALM2, and CALM3 in proliferating human teratoma cells revealed that CALM3 is at least 5-fold more actively transcribed than CALM1 or CALM2. The 5' untranslated regions of each CALM gene are necessary to recover full promoter activity in transfection assays, indicating post-transcriptional regulation of calmodulin levels. Nuclear run-on transcription assay, Northern blotting for mRNA abundance, luciferase reporter transfection with CALM promoter constructs ± 5'UTR in teratoma cells Cell Calcium High 9681195
2005 A functional SNP (−16C>T) in the core promoter of CALM1 decreases CALM1 transcription in vitro and in vivo. Inhibition of calmodulin in chondrogenic cells reduced expression of major cartilage matrix genes Col2a1 and Agc1, implicating the CALM1-mediated signaling pathway in chondrocyte differentiation and cartilage matrix production. Case-control association study; luciferase reporter assay for promoter activity in vitro; in vivo allele-specific transcription analysis; pharmacological calmodulin inhibition in chondrogenic cells with RT-PCR for Col2a1 and Agc1 Human Molecular Genetics Medium 15746150
2013 A missense mutation p.F90L in CALM1 encoding calmodulin was identified in a family with idiopathic ventricular fibrillation (IVF). The F90 residue is a highly conserved residue that mediates the direct interaction of CaM with target peptides, establishing that disruption of CaM–target interactions can cause life-threatening arrhythmia. Exome sequencing of affected family members; pedigree analysis; conservation analysis of F90 position Journal of the American College of Cardiology Medium 24076290
2014 RNAi-mediated knockdown of Calm1 (but not Calm2 or Calm3) in mouse precerebellar neurons caused defective tangential and radial migration, with neurons failing to reach target positions in the hindbrain. This established a gene-specific requirement for CALM1 in neuronal migration that cannot be compensated by the other calmodulin-encoding genes. Acute in vivo RNAi knockdown of individual Calm genes (shRNA), histological analysis of precerebellar neuron migration in mouse hindbrain Development Medium 25519244
2015 FMRP (Fmr1-encoded protein) associates with miR-181d, Map1b mRNA, and Calm1 mRNA in axons. FMRP mediates axonal delivery of miR-181d, which locally represses translation of Calm1 (and Map1b) in sensory neuron axons, negatively regulating axon elongation. NGF stimulation releases Calm1 mRNA from FMRP/miR-181d-repressing granules, promoting local calmodulin synthesis and axon elongation. Co-immunoprecipitation of FMRP with miR-181d/Map1b/Calm1; FMRP KO (Fmr1^I304N) and knockdown; axonal fractionation with protein quantification; miR-181d overexpression; NGF stimulation assays in primary sensory neurons Cell Reports Medium 26711345
2016 CALM1 (and CALM2/3) variants causing LQTS reduce CaM affinity for Ca2+ and cause a functionally dominant loss of Ca2+-dependent inactivation (CDI) of the cardiac L-type calcium channel CaV1.2. The novel E141G-CaM variant showed an 11-fold reduction in Ca2+ binding affinity and dominant loss of CaV1.2 CDI, mild NaV1.5 late current accentuation, but no effect on RyR2-mediated Ca2+ release. Whole-exome sequencing; Ca2+ binding affinity measurements; patch-clamp electrophysiology of CaV1.2, NaV1.5 in heterologous expression; intracellular Ca2+ release assay for RyR2 Circulation: Cardiovascular Genetics High 26969752
2017 The CALM1-F142L mutation in patient-derived iPSC-CMs causes prolonged repolarization with altered rate-dependency, severe impairment of Ca2+-dependent inactivation (CDI) of ICaL (increased inward current during plateau), and failure of repolarization adaptation at high pacing rates. These effects were reversed by verapamil (ICaL blocker). The mutation did not affect IKs, INaL, or intracellular Ca2+ store stability, placing the primary arrhythmogenic defect specifically at CaV1.2 CDI. iPSC-CM generation from CALM1-F142L patient; dynamic clamp (simulated IK1); patch-clamp for ICaL CDI, IKs, INaL, If; intracellular Ca2+ imaging; action potential modeling; pharmacological rescue with verapamil Cardiovascular Research High 28158429
2020 Heterozygous Calm1-N98S knock-in mice exhibit sinus bradycardia, QTc prolongation, QRS widening, and catecholaminergic bidirectional ventricular tachycardia. β-Adrenergic stimulation increased peak ICaL density, slowed ICaL inactivation, left-shifted ICaL activation, and increased late ICaL significantly more in mutant than wild-type ventricular myocytes. Both reentry and focal mechanisms (EADs in His-Purkinje fibers, DADs in ventricular myocytes) contribute to arrhythmogenesis, establishing β-adrenergically induced ICaL dysregulation as the primary mechanism of the long-QT phenotype. CRISPR/Cas9 knock-in mouse generation; ECG monitoring; optical voltage mapping; patch-clamp (ICaL, action potentials); fluorescence Ca2+ imaging; microelectrode recording of His-Purkinje fibers; pharmacological β-blocker/agonist treatment Circulation High 32929985
2024 A suppression-and-replacement (SupRep) gene therapy construct containing shRNAs targeting CALM1, CALM2, and CALM3 plus a shRNA-immune CALM1 cDNA shortened pathologically prolonged APD90 in CALM1-F142L, CALM2-D130G, and CALM3-D130G iPSC-CMs, demonstrating that a single construct can treat all calmodulinopathy variants regardless of which of the three CALM genes is mutated. shRNA knockdown efficiency testing in TSA201 cells; lentiviral transfection of SupRep construct into patient-derived iPSC-CMs; voltage-sensing dye measurement of APD90 Circulation: Arrhythmia and Electrophysiology Medium 39069900
2024 Cryo-EM structure of the UBR4–KCMF1–CALM1 complex (~1.3 MDa ring) revealed that CALM1 (calmodulin) is a structural cofactor of the UBR4 E4 ubiquitin ligase megacomplex, which extends K48-specific ubiquitin chains on substrate proteins. The architecture is conserved across eukaryotes with species-specific adaptations, and efficient substrate targeting requires both pre-ubiquitination and specific N-degrons with KCMF1 acting as substrate filter. Cryo-EM structural analysis; biochemical reconstitution; ubiquitination assays bioRxiv (preprint)preprint Medium bio_10.1101_2024.12.18.629163
2025 miR-202-3p directly targets Calm1 (validated by luciferase reporter assay) and suppresses Calm1 protein expression in murine lung tissue. In an LPS-induced ARDS mouse model, miR-202-3p overexpression reduced CALM1 protein levels, inactivated NF-κB/NLRP3 signaling, and attenuated pulmonary inflammation and edema, placing CALM1 upstream of the NF-κB/NLRP3 pathway in inflammatory lung injury. Luciferase reporter assay; Western blotting; immunohistochemistry; miR-202-3p agomir administration in C57BL/6 mice; LPS-induced ARDS model; measurement of NF-κB/NLRP3 signaling proteins Cell Biochemistry and Biophysics Medium 38635101
2025 Erianin (a natural compound) directly binds to CALM1 protein, enhancing its stability and subsequently increasing CAMKK2 phosphorylation. This CALM1/CAMKK2 axis activation promotes autophagy in 5-FU-resistant colorectal cancer cells, leading to tumor cell death and restored sensitivity to 5-FU. Drug-target binding assay; Western blotting for CALM1 stability and CAMKK2 phosphorylation; autophagy marker immunofluorescence; CCK8/EdU/Transwell proliferation and invasion assays; xenograft tumor model Chemico-Biological Interactions Medium 40976489
2025 miR-205-5p promotes proliferation, migration, and invasion of nasopharyngeal carcinoma cells by directly targeting and suppressing CALM1 expression, validated by dual luciferase reporter assay. Inhibition of CALM1 by miR-205-5p mediates its oncogenic effects in NPC cells. Dual luciferase reporter assay; MTT, colony formation, Transwell assays; qRT-PCR and Western blot; overexpression in NPC cell lines Critical Reviews in Immunology Low 39976516
2026 CALM1/2 de novo variant c.419A>T (p.E140V) causes a neurological phenotype (hypotonia, motor delay, intellectual disability, abnormal EEG) without cardiac arrhythmia. RNA-seq showed the variant allele predominantly produces frameshifted C-terminal truncations via splice donor gain/intron retention (without NMD), with only a minority producing p.E140V missense protein. C. elegans cmd-1 modeling showed E140V has qualitatively and quantitatively different phenotypes from the arrhythmia variant E141G, indicating distinct molecular mechanisms for cardiac vs. neurological calmodulinopathy. Next-generation sequencing; RNA-seq of patient blood (splice analysis); C. elegans cmd-1 genetic modeling with phenotypic comparison of E140V vs. E141G Human Molecular Genetics Medium 41467504
2026 Ribosome profiling of human left ventricle tissue revealed that CALM1 and CALM2 each contribute ~44–45% of total cardiac calmodulin protein, while CALM3 contributes only ~11%, despite CALM3 being more actively transcribed than CALM2 relative to protein output in some tissues. This differential translation efficiency explains why CALM3 missense variants are clinically less severe and subject to weaker negative selection (observed/expected ratio 0.29 vs. 0.11 for CALM1) than CALM1 variants. Ribosome profiling of left ventricle tissue (GTEx); RNA-seq from 49 tissues; gnomAD variant analysis; International Calmodulinopathy Registry clinical data Europace Medium 41846582
2024 Calmodulin missense variants in schizophrenia patients fall into two functional classes: (1) loss-of-function variants reducing Ca2+ affinity and impairing CaV1.2 gating (similar to but with smaller effect than LQTS variants), and (2) gain-of-function variants unexpectedly enhancing Ca2+ affinity with no impact on CaV1.2 gating. All schizophrenia-associated variants clustered in the C-terminal lobe of calmodulin. Large-scale sequencing (24,248 schizophrenia patients, 97,322 controls); Ca2+ affinity measurements; electrophysiological characterization of CaV1.2 gating bioRxiv (preprint)preprint Medium bio_10.1101_2024.05.22.24307674

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Analysis of protein-coding genetic variation in 60,706 humans. Nature 7914 27535533
1997 Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 2324 9278050
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1992 Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex. Science (New York, N.Y.) 950 1519061
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2001 Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circulation research 618 11397791
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
1997 Competitive binding of alpha-actinin and calmodulin to the NMDA receptor. Nature 505 9009191
2001 Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 500 11323678
1996 Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 465 8625412
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2002 Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 427 12408866
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2007 Cep97 and CP110 suppress a cilia assembly program. Cell 386 17719545
2009 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 375 19596235
1990 Smooth muscle calponin. Inhibition of actomyosin MgATPase and regulation by phosphorylation. The Journal of biological chemistry 374 2161834
2004 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. The Biochemical journal 372 14744259
2007 Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proceedings of the National Academy of Sciences of the United States of America 360 17620599
2013 A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. Journal of the American College of Cardiology 136 24076290
2016 Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circulation. Cardiovascular genetics 109 26969752
2017 Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes. Cardiovascular research 104 28158429
2005 A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Human molecular genetics 92 15746150
1993 Localization of the human bona fide calmodulin genes CALM1, CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3. Genomics 80 8314583
2015 FMRP-Mediated Axonal Delivery of miR-181d Regulates Axon Elongation by Locally Targeting Map1b and Calm1. Cell reports 65 26711345
1998 Characterization of the human CALM2 calmodulin gene and comparison of the transcriptional activity of CALM1, CALM2 and CALM3. Cell calcium 61 9681195
2021 C-Reactive Protein Apheresis as Anti-inflammatory Therapy in Acute Myocardial Infarction: Results of the CAMI-1 Study. Frontiers in cardiovascular medicine 58 33778017
1995 Cocaine-associated myocardial infarction. Clinical safety of thrombolytic therapy. Cocaine Associated Myocardial Infarction (CAMI) Study Group. Chest 47 7750312
2014 Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons. Development (Cambridge, England) 39 25519244
2005 The CALM1 core promoter polymorphism is not associated with hip osteoarthritis in a United Kingdom Caucasian population. Osteoarthritis and cartilage 37 16359877
2020 Elimination of Calm1 long 3'-UTR mRNA isoform by CRISPR-Cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice. RNA (New York, N.Y.) 33 32522888
2007 CaMi, a root-knot nematode resistance gene from hot pepper (Capsium annuum L.) confers nematode resistance in tomato. Plant cell reports 32 17310335
1994 Structure of the human CALM1 calmodulin gene and identification of two CALM1-related pseudogenes CALM1P1 and CALM1P2. European journal of biochemistry 32 7925473
2021 CALM1 promotes progression and dampens chemosensitivity to EGFR inhibitor in esophageal squamous cell carcinoma. Cancer cell international 30 33602237
2015 Common Variants in TRDN and CALM1 Are Associated with Risk of Sudden Cardiac Death in Chronic Heart Failure Patients in Chinese Han Population. PloS one 25 26196381
2020 Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation. Circulation 20 32929985
2023 Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer's Disease. Journal of Alzheimer's disease : JAD 16 36530083
2012 Risk stratification of ischaemic patients with implantable cardioverter defibrillators by C-reactive protein and a multi-markers strategy: results of the CAMI-GUIDE study. European heart journal 16 22285581
2008 Association of the CALM1 core promoter polymorphism with knee osteoarthritis in patients of Greek origin. Genetic testing 16 18452398
2018 The CAMI-score: A Novel Tool derived From CAMI Registry to Predict In-hospital Death among Acute Myocardial Infarction Patients. Scientific reports 15 29899463
2023 Changes in urinary exosomal protein CALM1 may serve as an early noninvasive biomarker for diagnosing diabetic kidney disease. Clinica chimica acta; international journal of clinical chemistry 13 37406751
2024 Single Construct Suppression and Replacement Gene Therapy for the Treatment of All CALM1-, CALM2-, and CALM3-Mediated Arrhythmia Disorders. Circulation. Arrhythmia and electrophysiology 11 39069900
2018 Association of CALM1 rs3179089 Polymorphism with Ischemic Stroke in Chinese Han Population. Neuromolecular medicine 11 29713907
2008 Lack of association between the CALM1 core promoter polymorphism (-16C/T) and susceptibility to knee osteoarthritis in a Chinese Han population. BMC medical genetics 10 18940010
2018 The association between rs12885713 polymorphism in CALM1 and risk of osteoarthritis: A meta-analysis of case-control studies. Medicine 8 30200150
2021 14q32.11 microdeletion including CALM1, TTC7B, PSMC1, and RPS6KA5: A new potential cause of developmental and language delay in three unrelated patients. American journal of medical genetics. Part A 7 33634591
1997 Assignment of TCF1, TGM1, CALM1, CKB, THBS1, B2M, and FES in Ateles paniscus chamek (Platyrrhini, Primates). Cytogenetics and cell genetics 7 9533020
2018 Association between the polymorphisms of CALM1 gene and osteoarthritis risk: a meta-analysis based on observational studies. Bioscience reports 6 30279205
2007 [Is polymorphism of CALM1 gene or growth hormone receptor gene associated with susceptibility to adolescent idiopathic scoliosis?]. Zhonghua yi xue za zhi 5 18001530
2021 CALM1 rs3179089 polymorphism might contribute to coronary artery disease susceptibility in Chinese male: a case-control study. Genes & genomics 4 34338988
2025 miR-205-5p Promotes the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells by Regulating CALM1. Critical reviews in immunology 3 39976516
2021 Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1. Journal of cardiovascular electrophysiology 3 34860437
2024 MiR-202-3p Targets Calm1 and Suppresses Inflammation in a Mouse Model of Acute Respiratory Distress Syndrome. Cell biochemistry and biophysics 2 38635101
2023 Case report of a child with long QT syndrome type 14 caused by CALM1 gene mutation and literature review. Molecular genetics & genomic medicine 1 37905352
2026 Phenotypic expansion of CALM1/2-associated disorders to include neurologic phenotypes without arrhythmia. Human molecular genetics 0 41467504
2026 Genetic and metabolic regulation of eggshell quality in aging hens: Integrated multi-omics insights into CYP7A1, CALM1, and cholic/stearic acid metabolism. International journal of biological macromolecules 0 41525860
2026 CALM1, CALM2, and CALM3 expression and translation efficiency provide insight into the severity of calmodulinopathy. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 0 41846582
2025 A Pilot Study of ANXA2, MED12, CALM1 and MAPK1 Gene Variants in Primary Hyperparathyroidism. Balkan journal of medical genetics : BJMG 0 40070855
2025 Erianin reverses 5-FU resistance by targeting CALM1/CAMKK2 and activating autophagy in colorectal cancer. Chemico-biological interactions 0 40976489
2025 Lactylation-Related Gene CALM1 Promotes Aortic Dissection via Immune Microenvironment Remodeling: Insights from Bioinformatics and Clinical Evidence. Journal of inflammation research 0 41181366
2025 Compact Calm1 promoter enables AAV mediated neuron-targeted expression in human iPSC-derived brain organoids. Scientific reports 0 41444788
2015 High genetic abundance of Rpi-blb2/Mi-1.2/Cami gene family in Solanaceae. BMC evolutionary biology 0 26424005
2001 Chromosomal mapping of calmodulin 1 (CALM1) and alpha-globin 1 genes (HBA1) in the bovine. Animal biotechnology 0 11808628