Affinage

GJA1

Gap junction alpha-1 protein · UniProt P17302

Length
382 aa
Mass
43.0 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GJA1 encodes connexin 43 (Cx43), the principal gap junction protein mediating intercellular communication through oligomeric channels permeable to ions, small molecules, and ATP, with critical roles in cardiac conduction, bone development, myometrial contractility, and glial-neuronal signaling (PMID:16155213, PMID:19176884, PMID:35312356, PMID:35634278). Full-length Cx43 is trafficked from the Golgi via microtubules to cell-cell junctions, a process dependent on an internally translated 20 kDa isoform (GJA1-20k) that stabilizes actin filaments and guides microtubule delivery; GJA1-20k also independently drives DRP1-independent mitochondrial fission that limits ischemia-reperfusion injury, and loss of GJA1-20k causes lethal cardiac arrhythmia in mice (PMID:28923791, PMID:32525845, PMID:34608863). Cx43 channel activity and turnover are regulated by multisite phosphorylation (Src, ERK, p38 MAPK, Pyk2, IP3R-dependent pathways), K63-linked ubiquitination counteracted by the deubiquitinases AMSH and USP8, and acetylation-dependent proteasomal degradation, with internalization further controlled by EHD1/Eps15 and ZO-1 interactions (PMID:25070368, PMID:29626091, PMID:32138615, PMID:32956670, PMID:26264759). Mutations in GJA1 cause oculodentodigital dysplasia (ODDD) through dominant-negative disruption of gap junction assembly or, in skin-affecting variants, through gain-of-function hemichannel activity leading to Ca²⁺ overload (PMID:12457340, PMID:25168385).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Establishing that GJA1 mutations cause ODDD resolved the genetic basis of a multi-organ developmental syndrome and implicated gap junction communication in craniofacial, dental, and limb patterning.

    Evidence Mutational screening of GJA1 coding regions in 17 ODDD families identified missense mutations and a codon duplication

    PMID:12457340

    Open questions at the time
    • Mechanism of dominant pathogenesis (haploinsufficiency vs. dominant-negative) was not resolved
    • Channel-level consequences of individual mutations were not measured
  2. 2005 High

    Demonstrating that the G60S Cx43 mutation acts as a dominant negative established that ODDD arises from disrupted gap junction assembly rather than simple loss of function, and showed Cx43 trafficking through the Golgi requires microtubules.

    Evidence ENU mutagenesis/positional cloning in mice (G60S) with in vitro electrophysiology; parallel live-imaging of Cx43-GFP trafficking with brefeldin A and nocodazole treatment

    PMID:16155213 PMID:16159960

    Open questions at the time
    • Whether all ODDD mutations share the dominant-negative mechanism was unknown
    • Post-Golgi vesicular carriers were heterogeneous and not molecularly defined
  3. 2005 High

    Zebrafish cx43 mutants revealed that Cx43-mediated local communication controls bone segment size, extending the role of Cx43 beyond mammalian gap junction coupling to skeletal morphogenesis.

    Evidence Genetic mapping and expression analysis of ENU-induced cx43 alleles in zebrafish fin rays

    PMID:15649473

    Open questions at the time
    • Downstream signals linking Cx43 communication to growth plate regulation were not identified
  4. 2007 Medium

    Identifying ZO-1 as a regulator of Cx43 internalization through a proteasome-sensitive interaction provided the first evidence that gap junction plaque size is controlled by scaffolding protein dynamics.

    Evidence Co-immunoprecipitation of Cx43–ZO-1, PDZ2 domain overexpression, proteasome inhibitor treatment with immunofluorescence

    PMID:17541973

    Open questions at the time
    • Single Co-IP direction without reciprocal validation
    • Identity of the proteasomal substrate controlling the interaction was not determined
  5. 2014 High

    Discovery that AMSH deubiquitinates K63-linked polyubiquitin on Cx43 and that gain-of-function hemichannel activity underlies keratitis-ichthyosis-deafness-like syndrome established ubiquitin editing and hemichannel gating as distinct regulatory axes of Cx43 biology.

    Evidence Reciprocal Co-IP, catalytically inactive AMSH mutant, siRNA with internalization/degradation assays for AMSH; patch-clamp hemichannel recording and Ca²⁺ imaging of G8V mutant in HEK293 cells for gain-of-function

    PMID:25070368 PMID:25168385

    Open questions at the time
    • Ubiquitin ligase(s) adding K63 chains to Cx43 were not identified
    • Whether hemichannel gain-of-function applies to other skin-affecting Cx43 mutations was untested
  6. 2015 Medium

    Multiple phosphorylation-dependent regulatory inputs were mapped: IP3R interaction promotes S279/282 phosphorylation to enhance gap junction permeability, while acetylation triggers proteasomal degradation and Hsc70 binding links Cx43 to cell cycle control.

    Evidence Co-IP of IP3R–Cx43 with site-directed mutagenesis and dye diffusion; HDAC/HAT assays with MG132 in tachypaced cardiomyocytes; Cx43-Hsc70 competition assays with cell cycle analysis

    PMID:25262337 PMID:26264759 PMID:26481195

    Open questions at the time
    • Direct acetylation sites on Cx43 were not mapped
    • Whether Hsc70-mediated cell cycle effects require gap junction channel activity was unclear
    • IP3R-Cx43 study from single lab without independent replication
  7. 2017 High

    Discovery that the internally translated GJA1-20k isoform stabilizes actin and guides microtubule-dependent delivery of full-length Cx43 to intercalated discs revealed a non-canonical trafficking mechanism and a channel-independent function for the GJA1 locus.

    Evidence AAV9-mediated GJA1-20k gene transfer in vivo, micropatterned cell pairing, actin stabilization assays, latrunculin A disruption, Co-IP of GJA1-20k with actin/tubulin

    PMID:28923791

    Open questions at the time
    • How GJA1-20k internal translation is regulated was unknown
    • Whether GJA1-20k acts as a monomer or oligomer was not determined
  8. 2018 Medium

    Src and downstream ERK-mediated phosphorylation at multiple tyrosine and serine residues was shown to drive gap junction internalization into connexisomes, while p38 MAPK phosphorylation at S368 impairs coupling during inflammation, mapping the kinase cascade controlling Cx43 disassembly.

    Evidence Phospho-specific antibodies with kinase inhibitors and live imaging; IL-1β/p38 MAPK inhibitor treatment with gap junction assays and isolated heart perfusion; USP8 deubiquitination studies

    PMID:29626091 PMID:29664174 PMID:33255329

    Open questions at the time
    • Temporal hierarchy of phosphorylation events during internalization was not resolved
    • How proteasomal versus lysosomal routes are differentially selected remained unclear
  9. 2020 High

    EHD1 was identified as a Cx43 endocytic partner bridged by Eps15, and Pyk2 was established as a direct Cx43 kinase at Y247/Y265/Y267/Y313, together defining the molecular machinery coupling phosphorylation and ubiquitination to gap junction internalization.

    Evidence Proteomic identification of EHD1 with reciprocal Co-IP, siRNA/OE in cardiomyocytes; in vitro phosphorylation screen with mass spectrometry and dye transfer in NRVMs and heart failure model

    PMID:32138615 PMID:32956670

    Open questions at the time
    • Whether EHD1 and Pyk2 act sequentially or in parallel during internalization was not tested
    • Structural basis of EHD1–Cx43 interaction was not defined
  10. 2020 High

    CRISPR disruption of the GJA1-20k internal translation start (M213L) proved that GJA1-20k is essential in vivo: mice lacking this isoform have halved Cx43 half-life, depleted gap junctions, and die from arrhythmia within weeks, establishing GJA1-20k as a critical auxiliary factor for cardiac conduction.

    Evidence CRISPR M213L knock-in mouse model with ECG, biochemical half-life assays, Western blot, immunofluorescence

    PMID:32525845

    Open questions at the time
    • Whether GJA1-20k deficiency affects non-cardiac tissues was not examined
    • Rescue by exogenous GJA1-20k was not demonstrated in vivo
  11. 2021 High

    GJA1-20k was shown to polymerize actin around mitochondria to drive rapid DRP1-independent fission (~45 s), reducing ROS generation and protecting against ischemia-reperfusion injury, defining a channel-independent cardioprotective mechanism.

    Evidence Live cell imaging with DRP1 knockout/inhibition, ROS measurement, mouse ischemia-reperfusion model

    PMID:34608863

    Open questions at the time
    • How GJA1-20k is recruited specifically to mitochondria rather than other organelles was not established
    • Whether GJA1-20k-mediated fission occurs in non-cardiac cells in vivo was not tested
  12. 2021 High

    Physical interaction of RyR2 with Cx43 hemichannels and the requirement for RyR-triggered Ca²⁺ elevation for hemichannel opening at diastolic potentials revealed a local Ca²⁺-dependent gating mechanism for hemichannel activation in cardiomyocytes.

    Evidence Co-IP, proximity ligation assay (<40 nm), whole-cell patch-clamp with Ca²⁺ clamp, RyR-mimicking inhibitory peptide

    PMID:31841141

    Open questions at the time
    • Stoichiometry and structural interface of the RyR2–Cx43 complex were not defined
    • Whether this mechanism operates during arrhythmogenic conditions in vivo was not shown
  13. 2022 High

    Cx43 hemichannels were established as mediators of paracrine toxicity: macrophage hemichannel ATP efflux drives fibroblast activation via P2RX4 in lung fibrosis, and astrocyte hemichannels mediate motor neuron death in ALS, defining hemichannel-dependent pathological signaling.

    Evidence Conditional macrophage Cx43 knockout with ATP efflux and bleomycin fibrosis model; astrocyte-specific Cx43 knockout in ALS mice plus hemichannel blockers (GAP19, tonabersat) in hiPSC motor neuron co-culture

    PMID:35312356 PMID:35634278

    Open questions at the time
    • Identity of the toxic factor(s) released through astrocyte hemichannels in ALS was not determined
    • Whether hemichannel blockade is sufficient versus elimination of both gap junctions and hemichannels was not fully dissected
  14. 2022 High

    CYLD deubiquitinase activity on plakoglobin was shown to promote desmoplakin/EB1-mediated microtubule delivery of Cx43 to cardiac cell membranes, connecting desmosomal integrity to gap junction formation through ubiquitin signaling.

    Evidence CYLD-knockout mice with cardiac fibrosis/heart failure assessment, Co-IP, ubiquitination assays

    PMID:36577382

    Open questions at the time
    • Whether CYLD acts directly at intercalated discs or indirectly via cytoplasmic plakoglobin pools was not resolved
  15. 2023 High

    Cryo-EM structures of Cx43 gap junction channels resolved three N-terminal helix conformations (GCN, PLN, FIN) and an α-to-π helix transition creating a lipid-accessible side opening, providing the first structural framework for understanding gating by lipids, pH, and the C-terminal tail.

    Evidence Cryo-EM in detergent and lipid nanodiscs with C-terminal truncation mutants, pH manipulation, and cholesteryl hemisuccinate treatment

    PMID:36805660

    Open questions at the time
    • How phosphorylation and ubiquitination of the C-terminus alter the conformational equilibrium structurally was not resolved
    • Hemichannel-specific structures were not obtained

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of hemichannel selectivity versus gap junction selectivity, the ubiquitin ligase(s) responsible for K63-linked Cx43 ubiquitination, and how the multiple GJA1 translation products (full-length, 20k, 11k) are coordinately regulated under physiological and pathological conditions.
  • No E3 ligase for Cx43 K63-polyubiquitination identified
  • Regulation of internal translation initiation for GJA1-20k and GJA1-11k is uncharacterized
  • Hemichannel-specific cryo-EM structure not yet available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 9 GO:0005198 structural molecule activity 4
Localization
GO:0005886 plasma membrane 9 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1500931 Cell-Cell communication 10 R-HSA-382551 Transport of small molecules 6 R-HSA-162582 Signal Transduction 5 R-HSA-9609507 Protein localization 5 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
AMSHCYLDEHD1ITPR1PYK2RYR2USP8ZO-1
Complex memberships
Cx43 hemichannel (connexon)Gap junction intercellular channel (Cx43 hexamer/dodecamer)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Missense mutations and a codon duplication in GJA1 (encoding Cx43) cause oculodentodigital dysplasia (ODDD), with mutations likely causing misassembly of gap junction channels or altering channel conduction properties. Mutational screening of 17 ODDD families, sequencing of GJA1 coding regions American Journal of Human Genetics High 12457340
2005 A G60S missense mutation in Cx43 acts in a dominant-negative fashion to disrupt gap junction assembly and function, causing ODDD-like phenotype in mice including syndactyly, enamel hypoplasia, craniofacial anomalies, and decreased bone mass. N-ethyl-N-nitrosourea mutagenesis screen, positional cloning, in vivo and in vitro studies of mutant Cx43 protein Development High 16155213
2005 Cx43 mutations (connexin43/cx43) in zebrafish cause defects in fin ray segment length, with cx43 expressed in cells flanking the germinal region and in osteoblasts at segment boundaries, indicating a critical role for local cell-cell communication in bone size regulation. Genetic mapping, expression analysis, identification of missense mutations in ENU-induced alleles, partial loss-of-function studies in zebrafish Developmental Biology High 15649473
2005 Cx43 and Cx26 are both routed through the Golgi apparatus prior to transport to the cell surface; Cx43-GFP delivery and gap junction regeneration requires microtubules (inhibited by nocodazole) while Cx26 transport does not; both connexins use similar post-Golgi carriers including heterogeneous vesicles and tubular extensions. Time-lapse fluorescence imaging of fluorescent-protein-tagged connexins, brefeldin A and nocodazole treatment, dominant-negative Sar1 GTPase expression, FRAP Journal of Cell Science High 16159960
2006 A GJA1 frameshift mutation (fs260, from 780-781del) causes ODDD with palmoplantar keratoderma; the mutant protein localizes to the ER and other intracellular compartments, reduces gap junction plaques formed by endogenous Cx43, and dominantly inhibits wild-type Cx43-mediated gap junctional conductance in a dose-dependent manner. Cell line expression studies, immunofluorescence, dual whole-cell patch-clamp, single patch capacitance recording, co-expression studies Journal of Biological Chemistry High 16891658
2007 The proteasome regulates internalization of Cx43 by modulating the interaction between Cx43 and ZO-1; this interaction occurs through the PDZ2 domain of ZO-1 and the C-terminus of Cx43; proteasome inhibition reduces the Cx43-ZO-1 interaction, causing Cx43 accumulation in large gap junction plaques at the plasma membrane. Co-immunoprecipitation, immunofluorescence, overexpression of PDZ2 domain, proteasome inhibitor treatment Journal of Cellular Biochemistry Medium 17541973
2009 The dominant Gja1(Jrt) mutation (G60S) reduces phosphorylated Cx43 species in the myometrium, reduces gap junctional coupling between myometrial smooth muscle cells to <15% of wild-type, impairs parturition, and prevents the normal pre-partum increase in phosphorylated Cx43. Western blotting, immunostaining, patch-clamp electrophysiology, in vitro uterine strip contraction assay Biology of Reproduction High 19176884
2013 Autosomal recessive Cx43 mutation R76H traffics to the plasma membrane and forms functional gap junction channels with reduced conductance; R33X mutation remains diffusely localized (including nucleus), fails to form functional channels, and exerts dominant/trans-dominant effects on wild-type Cx43 and Cx40, reducing their gap junction plaques. HeLa and NRK cell expression, dye transfer studies, electrical conductance analysis (N2a cells), immunofluorescence Journal of Cell Science High 23606748
2014 AMSH (a deubiquitinase) interacts with Cx43, mediates its deubiquitination (specifically reversing K63-linked polyubiquitin chains), and is recruited to gap junction plaques at the plasma membrane; decreasing Cx43 deubiquitination by siRNA depletion or catalytically inactive AMSH increases both internalization and degradation of Cx43. Co-immunoprecipitation, siRNA depletion, overexpression of catalytically inactive mutant, immunofluorescence, internalization/degradation assays FASEB Journal High 25070368
2014 The Cx43 G8V (Gly8Val) mutation in KHLS causes gain-of-function hemichannel activity: hemichannels have significantly more openings than wild-type at resting potential, facilitating Ca2+ influx and potentially leading to Ca2+ overload and accelerated keratinocyte apoptosis. Whole-exome sequencing, patch clamp, Ca2+ imaging, dye transfer, HEK293 cell expression Human Molecular Genetics High 25168385
2015 Cx43 interacts with heat shock cognate protein 70 (Hsc70) and competes with CDK inhibitor p27 for Hsc70 binding; Cx43 overexpression decreases Hsc70 in the cyclin D1-CDK4-p27 complex, preventing nuclear translocation of the complex and thereby suppressing G1/S cell cycle progression. Co-immunoprecipitation, overexpression studies, nuclear accumulation assays, cell cycle analysis Scientific Reports Medium 26481195
2015 Intracellular spermine prevents acid-induced uncoupling of Cx43 gap junction channels and enhances Cx43-mediated gap junctional communication in a concentration-dependent manner, as measured by electrophysiological patch-clamp recording. Whole-cell patch-clamp recording from paired Novikoff cells and HeLa-Cx43-EGFP transfectants Neuroreport Medium 26011388
2017 The GJA1-20k isoform (internally translated 20 kDa C-terminal isoform of Cx43) stabilizes filamentous actin, guides microtubule growth trajectories toward cell-cell junctions, and is required for delivery of full-length Cx43 hemichannels to cardiac intercalated discs; GJA1-20k complexes with both actin and tubulin. AAV9-mediated gene transfer in vivo, micropatterned cell pairing systems, actin stabilization assays, latrunculin A disruption, immunofluorescence, co-immunoprecipitation Circulation Research High 28923791
2017 Cx43 deficiency in osteocytes leads to apoptosis via caspase-3 activation; the mechanism involves reduction of pro-survival microRNA miR21, increased PTEN, and reduced phospho-Akt; only Cx43 constructs able to form gap junction channels can reverse Cx43-deficient cell death; apoptotic Cx43-deficient osteocytes release more RANKL and HMGB1, promoting osteoclastogenesis. Cx43 silencing in MLO-Y4 osteocytic cells, Cx43 transfection rescue, miR21 mimic/deletion, PTEN inhibition, caspase-3 inhibition, conditioned media osteoclastogenesis assay Aging Cell High 28317237
2018 Cx43 is phosphorylated at Y247, Y265, S279/282, S365, and S373 by Src kinase; Src activation promotes formation of connexisomes (internalized gap junctions) through ERK-mediated phosphorylation of S279/282; proteasomal and lysosomal inhibition have distinct effects on the Cx43 phospho-profile and gap junction disassembly. Live imaging, phospho-specific antibodies, specific kinase inhibitors, proteasome and lysosome inhibitors Biomolecules Medium 33255329
2018 USP8 (ubiquitin-specific peptidase 8) interacts with Cx43, deubiquitinates it (reducing both multiple monoubiquitination and polyubiquitination), and stabilizes Cx43 by preventing autophagy-mediated degradation; USP8 knockdown decreases Cx43 protein levels and suppresses intercellular communication. Co-immunoprecipitation, ubiquitination assays, USP8 knockdown, dye transfer assay Journal of Biological Chemistry Medium 29626091
2018 IL-1β activates p38 MAPK to upregulate Cx43 phosphorylation at Ser368, impairing cell-to-cell communication; blockade of p38 MAPK downregulates pS368-Cx43 and improves intercellular coupling and reduces QRS duration in experimental myocarditis. Cell culture with IL-1β treatment, p38 MAPK inhibitors, Western blotting, gap junction communication assay, isolated heart perfusion Journal of Cellular and Molecular Medicine Medium 29664174
2019 The N-terminus and first extracellular loop of the Cx43 hemichannel, together with the C-terminus, preclude ion conductance of the open Cx43 hemichannel; chimeras containing the N-terminus or first extracellular loop from Cx30 allow both dye uptake and ion conduction in Cx43 hemichannels. Chimera construction, mutagenesis of pore-lining residues, Xenopus oocyte expression, electrophysiology, molecular dynamics simulations Journal of Biological Chemistry High 31554662
2020 EHD1 (Eps15 homology domain-containing protein 1) is a novel interactor of Cx43 in the heart; EHD1 knockdown impairs Cx43 internalization; interaction of Cx43 with EHD1 is mediated by Eps15 and promoted by phosphorylation and ubiquitination of Cx43; EHD1 overexpression accelerates Cx43 internalization and exacerbates ischemia-induced lateralization. Proteomics, siRNA knockdown, overexpression, co-immunoprecipitation, immunofluorescence in isolated adult cardiomyocytes Circulation Research High 32138615
2020 GJA1-20k (the internally translated 20 kDa isoform of Cx43) is required for Cx43 trafficking and maintenance of Cx43 protein; without GJA1-20k, poorly trafficked cytoplasmic Cx43 has 50% shorter half-life and is degraded; GJA1-20k-deficient mice (M213L CRISPR model) have severely abnormal ECGs, reduced gap junctions, and die suddenly at 2-4 weeks. CRISPR M213L knock-in mouse model, electrocardiography, biochemical half-life assays, Western blotting, immunofluorescence Journal of Clinical Investigation High 32525845
2020 Mitochondrial transfer from donor hematopoietic stem and progenitor cells (HSPCs) to bone marrow stromal cells requires HSPC-expressed Cx43; Cx43-deficient HSPCs show reduced mitochondria transfer that is rescued by Cx43 re-expression; elevated intracellular ATP activates P2RX7 and reduces AMPK activity, increasing mitochondria transfer. Cx43-deficient chimeric mice, mitochondria transfer assays, rescue with Cx43 re-expression or isolated mitochondria, AMPK inhibition in vivo Blood High 32929449
2020 Cx43 loss via CRISPR knockout in breast cancer cells significantly reduces tunneling nanotube (TNT) length and number; ROCK, PKA, FAK, and p38 signaling pathways regulate TNT formation in a Cx43-dependent manner; conditioned medium from Cx43-expressing cells stimulates TNTs more potently than from KO cells. CRISPR/Cas9 Cx43 knockout, TNT length/number quantification, conditioned medium experiments, kinase inhibitor treatment Cancers Medium 33003486
2020 Ubiquitin signals Cx43 release in extracellular vesicles under basal conditions but appears dispensable during myocardial ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and vesicular secretion; myocardial ischemia impairs Cx43 secretion into circulating, intracardiac, and cardiomyocyte-derived vesicles. Cell-based approaches, animal models, human patient samples, Western blotting, ubiquitination analysis Life Science Alliance Medium 33097557
2021 Ryanodine receptor 2 (RyR2) physically interacts with Cx43 hemichannels (co-immunoprecipitation, proximity ligation <40 nm), and RyR activation combined with intracellular Ca2+ elevation is necessary for Cx43 hemichannel opening at negative diastolic membrane potential; a RyR-mimicking peptide (RyRHCIp) inhibits this RyR/Ca2+-triggered HC activation without affecting voltage-triggered activation. Whole-cell patch-clamp, co-immunoprecipitation, proximity ligation assay, immunocytochemistry, Cx43 knockdown, molecular modelling, Ca2+-clamp conditions Cardiovascular Research High 31841141
2021 GJA1-20k overexpression promotes mitochondria transmission from astrocytes to neurons via Cx43-containing tunneling nanotubes (Cx43-TnTs); GJA1-20k reduces phosphorylated Cx43 levels without affecting total Cx43, and enhances dendrite length and mitochondrial function in TBI-damaged neurons. Transwell astrocyte-neuron co-culture, quantitative PCR, Western blot, immunofluorescence, GJA1-20k overexpression Cellular and Molecular Neurobiology Medium 33728536
2021 GJA1-20k polymerizes actin around mitochondria to induce focal constriction sites and stimulate non-canonical DRP1-independent mitochondrial fission within ~45 seconds of GJA1-20k recruitment; GJA1-20k-induced smaller mitochondria have decreased ROS generation and provide protection against ischemia-reperfusion injury. Live cell imaging in human cells and mice, time-lapse mitochondrial fission assay, DRP1 knockout/inhibition, ROS measurement, mouse ischemia-reperfusion model eLife High 34608863
2020 GJA1-11k (the 11 kDa alternatively translated isoform of Cx43) preferentially localizes to the nucleus in HEK293FT cells and suppresses cell growth by limiting cell cycle progression from G0/G1 to S phase, independently of channel-forming full-length Cx43. Overexpression in HEK293FT cells, subcellular localization by fluorescence microscopy, cell cycle analysis Biomolecules Medium 32244859
2022 The deubiquitinase CYLD interacts with plakoglobin and removes K63-linked polyubiquitin chains from plakoglobin; deubiquitinated plakoglobin enhances interaction with the desmoplakin/EB1 complex at microtubule plus ends, promoting microtubule-dependent transport of Cx43 to the cell membrane; CYLD depletion in mice impairs cardiac gap junction formation and increases heart failure. CYLD-knockout mice, Co-immunoprecipitation, ubiquitination assays, cardiac fibrosis and heart failure assessment, Western blotting, immunofluorescence Cell Reports High 36577382
2022 Cx43 hemichannels in ALS astrocytes mediate astrocyte-to-motor neuron toxicity; astrocyte-specific Cx43 knockout in ALS mice slows disease progression and provides motor neuron protection; pharmacological blockade of Cx43 hemichannels (GAP19 or tonabersat) protects hiPSC-derived motor neurons from ALS astrocyte-mediated toxicity. Astrocyte-specific Cx43 knockout mouse model, hiPSC-derived astrocytes and motor neurons, pharmacological hemichannel blockade, electrophysiology, survival analysis PNAS High 35312356
2022 Macrophage Cx43 hemichannels mediate ATP efflux into the extracellular space; deletion of Cx43 in macrophages (MacΔCx43) decreases ATP efflux and reduces cytosolic calcium response in co-cultured fibroblasts via P2rx4; MacΔCx43 mice exhibit decreased bleomycin-induced lung fibrosis. Conditional macrophage Cx43 knockout, ATP efflux measurement, co-culture calcium imaging, P2rx4 fibroblast-specific deletion, bleomycin lung fibrosis model Frontiers in Immunology High 35634278
2023 Cryo-EM structures of Cx43 gap junction intercellular channels reveal three distinct N-terminal helix conformations (gate-covering/GCN, pore-lining/PLN, flexible intermediate/FIN); the conformational equilibrium shifts to GCN by cholesteryl hemisuccinates and to PLN by C-terminal truncations or pH changes; an α-to-π-helix transition in the first transmembrane helix creates a side opening to the membrane in FIN and PLN conformations. Cryo-electron microscopy in detergents and lipid nanodiscs, C-terminal truncation mutants, pH manipulation, cholesteryl hemisuccinate treatment Nature Communications High 36805660
2020 Pyk2 phosphorylates Cx43 at residues Y247, Y265, Y267, and Y313; Pyk2 can be activated by Src and active Pyk2 interacts with Cx43 at the plasma membrane; overexpression of Pyk2 increases Cx43 phosphorylation and decreases gap junctional intercellular communication; Pyk2 inhibition combined with Src inhibition restores GJIC. In vitro phosphorylation screen, mass spectrometry, Western blot, immunofluorescence, GJIC dye transfer in HeLaCx43 cells and NRVMs, animal model of heart failure Journal of Molecular and Cellular Cardiology High 32956670
2015 IP3 receptor (IP3R) physically interacts and co-localizes with Cx43 in ventricular cardiomyocyte gap junction plaques; IP3R activation promotes Cx43 phosphorylation at S279/282 and enhances gap junction permeability, while IP3R inhibition or silencing reduces both S279/282 phosphorylation and intercellular communication; site-directed mutagenesis of S282A inhibits GJ permeability while S279A promotes it. Co-immunoprecipitation, immunostaining, shRNA silencing, IP3R agonist/antagonist treatment, dye diffusion assay, site-directed mutagenesis, HEK293 cell expression Cell Communication and Signaling Medium 25262337
2015 Electrical stimulation of cardiomyocytes reduces Cx43 expression and cell-cell communication by an acetylation-dependent post-translational mechanism: HDAC activity is downregulated, leading to increased acetylation of Cx43 and proteasome-mediated Cx43 degradation without reduction in Cx43 mRNA; HAT inhibition maintains Cx43 levels and communication. Field stimulation of HL-1 cardiomyocytes, HDAC/HAT activity assays, proteasome inhibitor (MG132), HAT inhibitor (Anacardic Acid), RT-PCR, Western blot, chronic tachypacing dog model Journal of Molecular and Cellular Cardiology Medium 26264759

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Understanding the odd science of aging. Cell 1290 15734677
2009 Immunoglobulin G4: an odd antibody. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 623 19222496
2002 Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. American journal of human genetics 504 12457340
2005 Mitochondrial H(+) leak and ROS generation: an odd couple. Free radical biology & medicine 356 15589367
2009 GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Human mutation 213 19338053
2005 A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development (Cambridge, England) 199 16155213
2011 Functional consequences of abnormal Cx43 expression in the heart. Biochimica et biophysica acta 152 21839722
2017 Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging cell 117 28317237
2017 Intracellular trafficking pathways of Cx43 gap junction channels. Biochimica et biophysica acta. Biomembranes 111 28576298
2005 Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration. Journal of cell science 109 16159960
2014 Syndromic and non-syndromic disease-linked Cx43 mutations. FEBS letters 107 24434540
2005 Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins. Developmental biology 104 15649473
2018 Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer letters 92 30472182
2017 GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs. Circulation research 83 28923791
2003 Microglia activation influences dye coupling and Cx43 expression of the astrocytic network. Glia 82 12655594
2020 Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood 79 32929449
2005 Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. FEBS letters 79 16288748
2004 A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Human mutation 79 14974090
2003 The odd couple: signal transduction and endocytosis. Cellular and molecular life sciences : CMLS 78 14618253
2016 Antimicrobial Resistance in Mycobacterium tuberculosis: The Odd One Out. Trends in microbiology 77 27068531
2000 Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Blood 74 10910905
2004 Novel Connexin 43 (GJA1) mutation causes oculo-dento-digital dysplasia with curly hair. American journal of medical genetics. Part A 71 15108203
2010 Srs2: the "Odd-Job Man" in DNA repair. DNA repair 70 20096651
2020 Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells. Cancers 69 33003486
1996 Neurotrophin-4: the odd one out in the neurotrophin family. Neurochemical research 63 8873083
2021 Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway. Frontiers in pharmacology 59 34084134
2010 Immunolocalization of gap junction protein connexin43 (GJA1) in the human retina and optic nerve. Investigative ophthalmology & visual science 59 20375327
2013 A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family. Clinical genetics 58 23550541
2006 Functional characterization of a GJA1 frameshift mutation causing oculodentodigital dysplasia and palmoplantar keratoderma. The Journal of biological chemistry 56 16891658
2020 EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases. Circulation research 55 32138615
2022 Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS. Proceedings of the National Academy of Sciences of the United States of America 53 35312356
2013 Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system? Frontiers in pharmacology 53 24133447
2020 Auxiliary trafficking subunit GJA1-20k protects connexin-43 from degradation and limits ventricular arrhythmias. The Journal of clinical investigation 52 32525845
2005 A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly. American journal of medical genetics. Part A 50 15637728
2023 Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM. Nature communications 46 36805660
2015 miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells. Bioscience reports 44 26450928
2014 Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome. Human molecular genetics 44 25168385
2020 Src Regulation of Cx43 Phosphorylation and Gap Junction Turnover. Biomolecules 42 33255329
2008 Similar transcriptomic alterations in Cx43 knockdown and knockout astrocytes. Cell communication & adhesion 42 18649190
2021 GJA1-20K Enhances Mitochondria Transfer from Astrocytes to Neurons via Cx43-TnTs After Traumatic Brain Injury. Cellular and molecular neurobiology 41 33728536
2011 The gap junction protein Cx43 regulates B-lymphocyte spreading and adhesion. Journal of cell science 41 21750189
2008 Alterations in Cx43 and OB-cadherin affect breast cancer cell metastatic potential. Clinical & experimental metastasis 41 18193170
2009 A dominant loss-of-function GJA1 (Cx43) mutant impairs parturition in the mouse. Biology of reproduction 40 19176884
2010 Gap junction protein connexin43 (GJA1) in the human glaucomatous optic nerve head and retina. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 39 20934339
2019 Polymerase iota - an odd sibling among Y family polymerases. DNA repair 38 31805501
2020 Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes. Life science alliance 37 33097557
2014 AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 25070368
2005 Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD). European journal of medical genetics 37 16378922
2021 RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes. Cardiovascular research 36 31841141
2018 The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer. International journal of molecular sciences 34 29495625
2005 A novel mutation in the GJA1 gene in a family with oculodentodigital dysplasia. Archives of ophthalmology (Chicago, Ill. : 1960) 34 16219735
2018 Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression. Journal of molecular and cellular cardiology 33 29777691
2021 Protective mitochondrial fission induced by stress-responsive protein GJA1-20k. eLife 32 34608863
2015 Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin. Developmental dynamics : an official publication of the American Association of Anatomists 31 26434741
2015 Intracellular spermine prevents acid-induced uncoupling of Cx43 gap junction channels. Neuroreport 30 26011388
2006 Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma. Investigative ophthalmology & visual science 30 16638984
2017 Proteinase 3: the odd one out that became an autoantigen. Journal of leukocyte biology 29 28546501
2007 The proteasome regulates the interaction between Cx43 and ZO-1. Journal of cellular biochemistry 29 17541973
2003 Altered Cx43 expression during myocardial adaptation to acute and chronic volume overloading. Histology and histopathology 28 12647785
1997 Expression of the pair-rule gene odd Oz (odz) in imaginal tissues. Developmental dynamics : an official publication of the American Association of Anatomists 28 9142491
2021 Importance of Cx43 for Right Ventricular Function. International journal of molecular sciences 27 33498172
2013 Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. Journal of cell science 27 23606748
2020 An Alternatively Translated Connexin 43 Isoform, GJA1-11k, Localizes to the Nucleus and Can Inhibit Cell Cycle Progression. Biomolecules 26 32244859
2017 Inhibition of Cx43 mediates protective effects on hypoxic/reoxygenated human neuroblastoma cells. Journal of cellular and molecular medicine 26 28488330
2013 Decidual angiogenesis and placental orientation are altered in mice heterozygous for a dominant loss-of-function Gja1 (connexin43) mutation. Biology of reproduction 25 24048574
2018 The ubiquitin-specific protease USP8 deubiquitinates and stabilizes Cx43. The Journal of biological chemistry 24 29626091
2018 Up-regulated Cx43 phosphorylation at Ser368 prolongs QRS duration in myocarditis. Journal of cellular and molecular medicine 24 29664174
2023 MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury. Cell death discovery 23 36841811
2017 Aberrant Cx43 Expression and Mislocalization in Metastatic Human Melanomas. Journal of Cancer 23 28607585
2019 Structural determinants underlying permeant discrimination of the Cx43 hemichannel. The Journal of biological chemistry 22 31554662
2016 Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia. Molecular biology of the cell 22 27226478
2022 CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart. Cell reports 21 36577382
2021 Serine-threonine protein phosphatase regulation of Cx43 dephosphorylation in arrhythmogenic disorders. Cellular signalling 19 34217833
2015 Interaction of Cx43 with Hsc70 regulates G1/S transition through CDK inhibitor p27. Scientific reports 19 26481195
2014 Cx43 phosphorylation on S279/282 and intercellular communication are regulated by IP3/IP3 receptor signaling. Cell communication and signaling : CCS 19 25262337
2012 The G60S Cx43 mutant enhances keratinocyte proliferation and differentiation. Experimental dermatology 19 22775996
2012 A high-throughput assay for connexin 43 (Cx43, GJA1) gap junctions using codon-optimized aequorin. Assay and drug development technologies 19 23046406
2020 Involvement of GJA1 and Gap Junctional Intercellular Communication between Cumulus Cells and Oocytes from Women with PCOS. BioMed research international 18 32190671
2020 Inhibition of Pyk2 and Src activity improves Cx43 gap junction intercellular communication. Journal of molecular and cellular cardiology 18 32956670
2015 Roles of Cx43 and AKAP95 in ovarian cancer tissues in G1/S phase. International journal of clinical and experimental pathology 18 26823747
2014 Three novel GJA1 missense substitutions resulting in oculo-dento-digital dysplasia (ODDD) - further extension of the mutational spectrum. Gene 18 24508941
2018 Wnt/β-catenin signaling enhances transcription of the CX43 gene in murine Sertoli cells. Journal of cellular biochemistry 17 30417410
2015 To beat or not to beat: degradation of Cx43 imposes the heart rhythm. Biochemical Society transactions 17 26009194
2014 Pathological implications of Cx43 down-regulation in human colon cancer. Asian Pacific journal of cancer prevention : APJCP 17 24815435
2012 Electrophysiology of single and aggregate Cx43 hemichannels. PloS one 17 23112846
2022 Microbial production of odd-chain fatty acids. Biotechnology and bioengineering 16 36522132
2020 Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes. Biomolecules 16 33066499
2015 Increased expression of CX43 on stromal cells promotes leukemia apoptosis. Oncotarget 16 26517241
2010 Novel mutations in the connexin43 (GJA1) and GJA1 pseudogene may contribute to nonsyndromic hearing loss. Human genetics 16 20130915
2022 Upregulated miR-206 Aggravates Deep Vein Thrombosis by Regulating GJA1-Mediated Autophagy of Endothelial Progenitor Cells. Cardiovascular therapeutics 15 35360546
2021 Construction of a lncRNA/pseudogene-hsa-miR-30d-5p-GJA1 regulatory network related to metastasis of pancreatic cancer. Genomics 15 33839271
2019 Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis. Cells 15 31652649
2015 Acetylation mediates Cx43 reduction caused by electrical stimulation. Journal of molecular and cellular cardiology 15 26264759
2014 On the role of the gap junction protein Cx43 (GJA1) in human cardiac malformations with Fallot-pathology. a study on paediatric cardiac specimen. PloS one 15 24751918
2009 A case of oculodentodigital dysplasia syndrome with novel GJA1 gene mutation. Japanese journal of ophthalmology 15 19847613
2022 GJA1-20k and Mitochondrial Dynamics. Frontiers in physiology 14 35399255
2022 Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury. Frontiers in immunology 14 35634278
2022 GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels. International journal of molecular sciences 14 36362410
2024 Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels. The Journal of clinical investigation 13 39480488
2015 Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients. The Biochemical journal 13 26349540