Affinage

GJA1

Gap junction alpha-1 protein · UniProt P17302

Length
382 aa
Mass
43.0 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GJA1 encodes connexin 43 (Cx43), the principal connexin forming gap junctions and hemichannels that mediate intercellular and cell-membrane communication, with roles spanning cardiac electrical coupling, vascular signaling, immunity, bone, and the nervous system (PMID:33621213, PMID:35312356, PMID:39982706). Cx43 is trafficked through the Golgi to the plasma membrane along microtubules, a route distinct from the microtubule-independent delivery of other connexins (PMID:16159960); this trafficking is governed by GJA1-20k, an internally translated short isoform that stabilizes actin filaments to guide microtubule trajectories toward cell-cell borders, controls oligomerization of full-length Cx43 hexamers, and is required for normal Cx43 half-life and channel delivery (PMID:28923791, PMID:32525845, PMID:29467255). GJA1-20k additionally targets mitochondria, where it drives microtubule-based mitochondrial transport, increases biogenesis, and polymerizes peri-mitochondrial actin to drive DRP1-independent fission, reducing ROS and protecting the heart against ischemia/reperfusion injury (PMID:30333316, PMID:29163229, PMID:34608863). Cryo-EM defines the channel gating mechanism through interconverting N-terminal helix conformations and an α-to-π TM1 transition, while the N-terminus, first extracellular loop, and C-terminus set permeant selectivity (PMID:36805660, PMID:31554662). Channel and hemichannel activity is tuned by multi-site C-terminal phosphorylation by Akt, Src/ERK, Pyk2, p38 MAPK, and CK1 (controlling ZO-1 binding, conductance, gating, and connexisome-mediated internalization) and by intracellular Ca2+ released from RyR2 and IP3R, which physically associate with Cx43 (PMID:24508467, PMID:33255329, PMID:31841141, PMID:32956670, PMID:29664174, PMID:25262337). Cx43 turnover proceeds through Nedd4-mediated ubiquitination recognized by the endocytic adaptors Eps15 and EHD1, counteracted by USP8 deubiquitination, and is further modulated by acetylation and S-nitrosylation (PMID:19835873, PMID:32138615, PMID:29626091, PMID:26264759, PMID:33384302). Beyond channel coupling, Cx43 mediates contact-dependent mitochondrial transfer between cells, selective sorting of structured miRNAs into extracellular vesicles, formation of tunneling nanotubes carrying signaling cargo, and a C-terminus-dependent, channel-independent activation of Rap1 driving B-cell spreading (PMID:32929449, PMID:35593040, PMID:21750189, PMID:39480488). Dominant-negative and gain-of-function GJA1 mutations cause oculodentodigital dysplasia and related disorders, with phenotypic severity tracking the specific channel/trafficking defect of each mutation (PMID:16155213, PMID:16891658, PMID:23606748, PMID:25168385).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established that Cx43, unlike other connexins, depends on microtubules for its Golgi-to-membrane delivery, defining a connexin-specific trafficking route.

    Evidence Live-cell time-lapse imaging with brefeldin A, nocodazole, and FRAP comparing Cx43 and Cx26

    PMID:16159960

    Open questions at the time
    • Did not identify the molecular adaptors linking Cx43 to microtubules
    • Mechanism of plaque insertion not resolved
  2. 2009 Medium

    Identified the ubiquitin ligase and endocytic adaptor that target Cx43 for degradation, defining the entry point of regulated Cx43 turnover.

    Evidence Co-IP and siRNA knockdown of Nedd4 and Eps15 with immunofluorescence

    PMID:19835873

    Open questions at the time
    • Lysosomal vs proteasomal fate not fully resolved
    • Phospho-dependence of ubiquitination not defined here
  3. 2014 Medium

    Resolved how phosphorylation orchestrates gap junction enlargement versus turnover, ordering Akt, MAPK, and Src actions on the C-terminus.

    Evidence Phospho-specific antibodies, live imaging, kinase inhibitors with model integration

    PMID:24508467

    Open questions at the time
    • No in vitro reconstitution of phospho-state transitions
    • Direct kinase-substrate stoichiometry unmeasured
  4. 2017 High

    Discovered GJA1-20k as an actin-stabilizing, microtubule-guiding isoform that delivers Cx43 to junctions and organizes mitochondrial transport, reframing Cx43 trafficking around an internal translation product.

    Evidence AAV9 gene transfer, micropatterned pairing, latrunculin A, co-IP, and high-resolution/EM imaging with MTBD mutagenesis

    PMID:28923791 PMID:29163229

    Open questions at the time
    • Regulation of internal translation start usage not fully defined
    • Stoichiometry of GJA1-20k:full-length Cx43 complexes unknown
  5. 2018 High

    Showed GJA1-20k controls full-length Cx43 hexamer oligomerization and is suppressed during EMT, linking isoform regulation to a rate-limiting trafficking step.

    Evidence TGF-β-induced EMT, NativePAGE oligomerization assay, superresolution microscopy, ectopic expression

    PMID:29467255

    Open questions at the time
    • Molecular trigger of Smad3/ERK suppression of GJA1-20k not fully mapped
    • Whether oligomerization defect is sufficient for disease unknown
  6. 2018 High

    Demonstrated GJA1-20k targets mitochondria to boost biogenesis and confer cardioprotection, extending Cx43 biology beyond intercellular coupling.

    Evidence AAV9 gene transfer, mitochondrial fractionation, respiration and infarct-size measurements in mice

    PMID:30333316

    Open questions at the time
    • Direct outer-membrane binding partners not identified
    • Link between biogenesis and reduced ROS not mechanistically dissected
  7. 2020 High

    Genetically proved GJA1-20k is required for full-length Cx43 stability and cardiac viability, establishing the isoform as essential rather than accessory.

    Evidence CRISPR M213L knock-in mouse (blocks GJA1-20k translation), half-life measurement, ECG, immunofluorescence

    PMID:32525845

    Open questions at the time
    • Mechanism by which GJA1-20k extends cytoplasmic Cx43 half-life unresolved
    • Tissue-specific dependence not fully characterized
  8. 2020 Medium

    Extended the degradation pathway by identifying EHD1 as an Eps15-linked adaptor driving Cx43 internalization, and identified USP8 as the opposing deubiquitinase.

    Evidence Co-IP, knockdown/overexpression, dye transfer, ubiquitination assays in cardiomyocytes and cell lines

    PMID:29626091 PMID:32138615

    Open questions at the time
    • Coordination between USP8 and Nedd4/Eps15/EHD1 in time and space not defined
    • Single-lab observations without reciprocal cross-validation
  9. 2021 High

    Revealed GJA1-20k drives DRP1-independent mitochondrial fission via peri-mitochondrial actin polymerization, defining a non-canonical fission mechanism.

    Evidence Live-cell imaging with temporal resolution, DRP1 inhibition/KO epistasis, ROS and infarct measurements in human cells and mice

    PMID:34608863

    Open questions at the time
    • Force-generating partners at constriction sites not identified
    • How actin recruitment is spatially targeted to mitochondria unclear
  10. 2021 High

    Defined RyR2-coupled, Ca2+-triggered hemichannel activation at the intercalated disc as a pro-arrhythmic mechanism in failing hearts.

    Evidence Patch-clamp, co-IP, proximity ligation, siRNA, and Gap19/peptide inhibition across murine, porcine, and human cardiomyocytes

    PMID:31841141 PMID:33621213

    Open questions at the time
    • Structural basis of RyR2-Cx43 coupling not resolved
    • Therapeutic window for hemichannel blockade undefined
  11. 2023 High

    Provided the structural framework for channel gating by capturing distinct N-terminal helix conformations and an α-to-π TM1 transition opening a membrane-facing portal.

    Evidence Cryo-EM in detergent and nanodiscs with C-terminal truncations and pH modulation

    PMID:36805660

    Open questions at the time
    • Conformational states not directly linked to specific phospho-marks
    • Hemichannel-specific gating structure not captured
  12. 2025 High

    Connected hemichannel function to vascular signaling by showing TRPV4-eNOS-driven S-nitrosylation opens Cx43 hemichannels in endothelial lipid rafts to mediate vasodilation.

    Evidence Proximity ligation, patch-clamp, Ca2+ imaging, lipid raft disruption, and intravital/ex vivo vascular readouts

    PMID:39982706

    Open questions at the time
    • Specific nitrosylated cysteines not pinpointed in this context
    • Crosstalk with phospho-regulation of the same hemichannels unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory layers — phosphorylation, ubiquitination, acetylation, S-nitrosylation, GJA1-20k isoform control, and Ca2+ gating — are integrated in a single cell to set gap junction versus hemichannel versus non-channel output remains unresolved.
  • No unified model linking PTM combinations to defined channel states
  • Quantitative interplay of competing trafficking and degradation routes unknown
  • Determinants selecting channel vs non-channel (Rap1, miRNA-sorting, TNT) functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 3 GO:0003723 RNA binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 3 GO:0005856 cytoskeleton 3 GO:0005794 Golgi apparatus 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5357801 Programmed Cell Death 1
Partners
EHD1EPS15ITPR1NEDD4RYR2SRCUSP8ZO-1
Complex memberships
Cx43 gap junction channelCx43 hemichannel

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Akt phosphorylates Cx43 at S373, eliminating interaction with ZO-1 and allowing gap junctions to enlarge; subsequently MAPK and Src phosphorylate Cx43 to initiate turnover via formation of connexisomes (internalized gap junctions) or gap junction 'unzipping'. Phosphorylation-status specific antibodies, live imaging, kinase inhibitors, model integration with new experimental data FEBS letters Medium 24508467
2020 Src activation promotes formation of connexisomes via ERK-mediated phosphorylation of Cx43 at S279/282; proteasome inhibition rapidly restores gap junctions and dramatically alters the Cx43 phospho-profile; lysosomal inhibition nearly eliminates Y247 and Y265 phosphorylation, indicating multiple phosphorylation-regulated disassembly routes. Live imaging, specific kinase inhibitors, phospho-specific antibodies, proteasome and lysosome inhibitors Biomolecules Medium 33255329
2009 Nedd4 ubiquitin ligase ubiquitinates Cx43; ubiquitinated Cx43 is recognized by the endocytic adaptor Eps15 through its ubiquitin-interacting motif (UIM), targeting Cx43 to the endocytic pathway. siRNA depletion of Nedd4 reduces Cx43 ubiquitination; depletion of Eps15 causes Cx43 accumulation at the plasma membrane. Co-immunoprecipitation, siRNA knockdown, immunofluorescence Experimental cell research Medium 19835873
2020 EHD1 interacts with Cx43 via Eps15 and promotes Cx43 internalization; this interaction is mediated by phosphorylation and ubiquitination of Cx43. EHD1 knockdown impairs Cx43 internalization and preserves gap junction coupling in cardiomyocytes; EHD1 overexpression accelerates Cx43 internalization and exacerbates ischemia-induced lateralization of Cx43. Co-immunoprecipitation, knockdown, overexpression, immunofluorescence in cardiomyocytes Circulation research Medium 32138615
2018 USP8 (ubiquitin-specific peptidase 8) directly interacts with and deubiquitinates Cx43, reducing both monoubiquitination and polyubiquitination, thereby preventing autophagy-mediated degradation of Cx43. USP8 knockdown reduces Cx43 protein levels and suppresses intercellular communication. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, dye transfer assay The Journal of biological chemistry Medium 29626091
2005 Both Cx43 and Cx26 are routed through the Golgi apparatus prior to plasma membrane delivery; Cx43-GFP delivery and gap junction regeneration require microtubules (inhibited by nocodazole), whereas Cx26 delivery is microtubule-independent. FRAP revealed Cx26 is more mobile within gap junction plaques than Cx43. Live-cell fluorescence time-lapse imaging, brefeldin A treatment, nocodazole treatment, FRAP Journal of cell science High 16159960
2017 GJA1-20k, an internally translated 20 kDa isoform of Cx43 lacking the N-terminus, stabilizes actin filaments, which in turn guides microtubule growth trajectories toward cell-cell junctions, increasing Cx43 hemichannel delivery to cardiac intercalated discs. GJA1-20k complexes with both actin and tubulin. AAV9-mediated gene transfer in vivo, micropatterned cell pairing, actin polymerization inhibition (latrunculin A), co-immunoprecipitation, confocal imaging Circulation research High 28923791
2018 GJA1-20k targets to cardiac mitochondria, associates with the outer mitochondrial membrane, increases mitochondrial biogenesis, reduces mitochondrial membrane potential and ROS production, and protects hearts against ischemia/reperfusion injury. Endogenous GJA1-20k is upregulated by ischemia/reperfusion stress. AAV9-mediated gene transfer, mitochondrial fractionation, respiration measurements, infarct size quantification in mouse models JCI insight High 30333316
2017 GJA1-20k localizes to the interface between mitochondria and microtubules and facilitates microtubule-based mitochondrial transport to the cell periphery; the microtubule-binding domain (MTBD) of GJA1-20k is essential for this transport function. GJA1-20k rescues mitochondrial network fragmentation under oxidative stress. High-resolution fluorescence imaging, electron microscopy, mutagenesis of MTBD, hydrogen peroxide stress Frontiers in physiology High 29163229
2020 GJA1-20k is required for full-length Cx43 trafficking; mice with M213L mutation in Cx43 (preventing GJA1-20k translation) have severely reduced Cx43 protein due to 50% shorter half-life of cytoplasmic Cx43, reduced gap junctions, abnormal ECGs, and die suddenly at 2–4 weeks. CRISPR knock-in mouse model, biochemical half-life measurement, electrocardiography, immunofluorescence The Journal of clinical investigation High 32525845
2018 During epithelial-mesenchymal transition (EMT), GJA1-20k is suppressed in a Smad3- and ERK-dependent manner, leading to retention of full-length Cx43 (GJA1-43k) at the Golgi; GJA1-20k regulates GJA1-43k hexamer oligomerization, a limiting step in Cx43 trafficking, and ectopic GJA1-20k rescues gap junction formation without halting EMT. TGF-β-induced EMT, biochemical fractionation, NativePAGE, superresolution microscopy, ectopic expression Molecular biology of the cell High 29467255
2021 GJA1-20k polymerizes actin around mitochondria, inducing focal constriction sites and driving mitochondrial fission independent of DRP1 (non-canonical fission). This occurs within ~45 s of GJA1-20k actin recruitment. GJA1-20k-induced smaller mitochondria have decreased ROS generation and protect hearts against ischemia-reperfusion injury. Live-cell imaging, CRISPR/mutagenesis, DRP1 inhibition, ROS measurement, infarct size quantification in human cells and mice eLife High 34608863
2023 Cryo-EM structures of Cx43 gap junction intercellular channels revealed three N-terminal helix conformations: gate-covering (GCN), pore-lining (PLN), and flexible intermediate (FIN). Cholesteryl hemisuccinates shift the equilibrium to GCN; C-terminal truncations and pH changes shift it to PLN. An α-to-π helix transition in TM1 creates a side opening to the membrane in FIN and PLN conformations. Cryo-EM structural determination in detergents and lipid nanodiscs, C-terminal truncation mutants, pH modulation Nature communications High 36805660
2019 The N-terminus and first extracellular loop of Cx43, together with the C-terminus, determine permeant discrimination of the Cx43 hemichannel. Cx43/Cx30 chimeras containing the Cx30 N-terminus or first extracellular loop displayed both dye uptake and ionic conductance, unlike WT Cx43. Inhibitor potency is permeant-dependent. Chimera construction, mutagenesis, Xenopus oocyte expression, electrophysiology, dye uptake, molecular dynamics simulation The Journal of biological chemistry High 31554662
2021 Cx43 hemichannels are activated by intracellular Ca2+ release from ryanodine receptors (RyR2) at diastolic membrane potential (-70 mV); Cx43 and RyR2 physically interact (<40 nm proximity, co-immunoprecipitation). A conserved RyR-mimicking peptide (RyRHCIp) inhibits RyR/Ca2+-triggered hemichannel activation but not voltage-triggered activation. Whole-cell patch-clamp, co-immunoprecipitation, proximity ligation assay, Cx43 siRNA knockdown, molecular modelling Cardiovascular research High 31841141
2021 Cx43 hemichannels at the intercalated disc are activated during diastolic Ca2+ release in ventricular cardiomyocytes; hemichannel opening involves Ca2+ entry and coupling to Ca2+ release microdomains, contributing to delayed afterdepolarizations and triggered action potentials. Increased hemichannel activity contributes to electrical instability in failing human hearts. Electrophysiology, live imaging, super-resolution microscopy, pharmacological Gap19 inhibition in murine, porcine, and human cardiomyocytes The Journal of clinical investigation High 33621213
2005 The ODDD-linked G60S Cx43 mutant acts in a dominant-negative fashion to disrupt gap junction assembly and function in vivo and in vitro. N-ethyl-N-nitrosourea mutagenesis screen, positional cloning, in vitro functional assays, in vivo mouse model Development (Cambridge, England) High 16155213
2006 The ODDD-linked frameshift mutant fs260 (780-781del) localizes to the ER and intracellular compartments, fails to form gap junctions, and exerts a dominant-negative effect on wild-type Cx43 reducing gap junctional conductance by >60% at a 1:1 expression ratio. The aberrant 46 amino acids of the frameshift are responsible for the dominant-negative effect. Dual whole-cell patch-clamp, single patch capacitance recordings, co-expression studies, immunofluorescence The Journal of biological chemistry High 16891658
2013 The recessive R33X truncation mutant fails to form functional channels and exerts trans-dominant effects reducing gap junction plaques of co-expressed Cx43 and Cx40; the R76H mutant traffics to plasma membrane and forms functional channels but with reduced conductance, without negative effects on co-expressed connexins. Two distinct molecular mechanisms explain why R33X causes greater disease burden than R76H. Dye transfer assays, electrical conductance analysis (patch-clamp), immunofluorescence in HeLa and N2a cells Journal of cell science High 23606748
2014 GJA1 G8V mutation (KHLS syndrome) causes a gain-of-function in Cx43 hemichannel activity: the mutant forms functional gap junctions normally but the hemichannel has significantly more openings than WT, facilitating increased Ca2+ influx at resting potential, potentially leading to cytoplasmic Ca2+ overload and keratinocyte apoptosis. Patch clamp, Ca2+ imaging, microinjection dye transfer, immunofluorescence in HEK293 cells Human molecular genetics High 25168385
2018 Casein kinase 1 (CK1) phosphorylates Cx43 in normoxia; phospho-mimicking (CK1-D) but not phospho-null (CK1-A) mutants show high voltage-sensitivity and variable permselectivity. Both mutants display resistance to acidification-induced junctional uncoupling and hemichannel openings at normal external calcium. Multiple channel open states with increased overall conductivity were observed. Patch-clamp electrophysiology, dye injection, site-directed mutagenesis of CK1-targeted serines International journal of molecular sciences Medium 29867029
2020 Pyk2 phosphorylates Cx43 at Y247, Y265, Y267, and Y313 (identified by mass spectrometry); active Pyk2 is activated by Src and interacts with Cx43 at the plasma membrane. Overexpression of Pyk2 increases Cx43 phosphorylation and decreases gap junctional intercellular communication; combined Src and Pyk2 inhibition is required to fully restore GJIC. In vitro phosphorylation screen, mass spectrometry, Western blot, immunofluorescence, dye transfer assay, siRNA knockdown, overexpression in HeLa and NRVM cells Journal of molecular and cellular cardiology High 32956670
2018 IL-1β activates p38 MAPK to upregulate phosphorylation of Cx43 at Ser368, impairing cell-to-cell communication and prolonging QRS duration. Blockade of p38 MAPK reverses these effects in experimental autoimmune myocarditis. Western blot, p38 MAPK inhibition, isolated heart perfusion, gap junctional coupling assay Journal of molecular and cellular cardiology Medium 29664174
2014 IP3 receptor (IP3R) physically interacts with Cx43 at gap junction plaques (co-immunoprecipitation, co-localization) and regulates Cx43 phosphorylation at S279/282. IP3R activation promotes and inhibition suppresses gap junction permeability; S282A mutation inhibits S279/282 phosphorylation and gap junction permeability. Co-immunoprecipitation, immunostaining, dye transfer (6-CFDA), site-directed mutagenesis, IP3R siRNA knockdown in neonatal rat and adult mouse cardiomyocytes Cell communication and signaling : CCS Medium 25262337
2015 Electrical stimulation of cardiomyocytes increases acetylation of Cx43, targeting it for proteasomal degradation and reducing Cx43 expression and cell-cell communication. HDAC activity is downregulated while HAT activity is unchanged; HAT inhibitor (Anacardic Acid) maintains Cx43 levels and communication. Cx43 acetylation was also observed in vivo in dogs with chronic tachypacing. Electrical field stimulation, HDAC/HAT activity assay, proteasomal inhibition (MG132), immunoblot, dye transfer, in vivo dog model Journal of molecular and cellular cardiology Medium 26264759
2017 Cx43 in osteocytes regulates survival via the miR21/PTEN/Akt pathway: Cx43-deficient osteocytic cells have reduced miR21, increased PTEN, and reduced phospho-Akt, leading to caspase-3-mediated apoptosis. Only Cx43 constructs capable of forming gap junction channels reverse cell death. Cx43-deficient apoptotic cells release RANKL and HMGB1 via caspase-3, promoting osteoclastogenesis through HMGB1-RAGE interaction. siRNA knockdown, transfection rescue, caspase-3 inhibition, PTEN inhibition, miR21 mimic/deletion, conditioned media assay, miR21fl/fl mouse model Aging cell High 28317237
2020 Mitochondrial transfer from hematopoietic stem and progenitor cells (HSPCs) to bone marrow mesenchymal stromal cells is cell-contact dependent and mediated by HSPC Cx43. Cx43-deficient HSPCs show reduced mitochondrial transfer; re-expression of Cx43 rescues transfer. Elevated intracellular ATP activates P2RX7 and reduces AMPK activity in HSPCs, dramatically increasing mitochondrial transfer. Cx43-deficient chimeric mice, re-expression rescue, mitochondria tracking, ATP/P2RX7/AMPK pathway analysis, bone marrow transplantation Blood High 32929449
2022 Cx43 directly binds to specific miRNAs (including miR-133b) containing stable secondary structure elements and facilitates their selective sorting into extracellular vesicles, as well as delivery of EV-miRNAs into recipient cells. Cx43-mediated EV-miRNA sorting modulates autophagy in recipient cells. Co-immunoprecipitation (Cx43-miRNA interaction), RNA-binding assays, Cx43 KO/OE, autophagy readout EMBO reports Medium 35593040
2022 Cx43 loss-of-function in ALS astrocytes: astrocyte-specific Cx43 knockout slows ALS disease progression, protects motor neurons, and improves survival. In human iPSC-derived ALS astrocytes, Cx43 is upregulated and Cx43 hemichannels are enriched at the membrane; pharmacological hemichannel blockade with GAP19 or tonabersat provides neuroprotection and reduces neuronal hyperexcitability. Astrocyte-specific Cx43 KO mouse model, hiPSC-derived astrocytes, pharmacological hemichannel blockade, electrophysiology, survival analysis Proceedings of the National Academy of Sciences of the United States of America High 35312356
2011 Cx43 C-terminal domain is required for BCR-, LFA-1-, and CXCL12-mediated Rap1 GTPase activation and B-cell spreading; C-terminal truncated Cx43 fails to restore Rap1 activation and spreading, identifying a non-channel signaling role for the Cx43 C-terminus in B-cell adhesion and spreading. shRNA knockdown, transfection of WT vs. C-terminal truncated Cx43-GFP, Rap1 activation assay, cell spreading assay, adhesion assay Journal of cell science Medium 21750189
2020 Cx43 CRISPR knockout in breast cancer cells significantly reduces tunneling nanotube (TNT) length and number; conditioned medium from Cx43-expressing cells stimulates TNTs more potently than from KO cells; ROCK, PKA, FAK, and p38 inhibition stimulates TNTs more potently in Cx43 KO cells than WT, indicating Cx43 regulates TNT formation via these cancer signaling pathways. CRISPR/Cas9 KO, TNT morphometric analysis, conditioned medium assay, kinase inhibitor panel Cancers Medium 33003486
2005 Cx43 expression is regulated by mechanical stretch via beta1-integrin signaling: stretch upregulates Cx43 in cardiomyocytes grown on native type I collagen via beta1 integrin activation (blocked by anti-beta1 antibody but not anti-beta3). RGD peptide or MnCl2-mediated integrin activation mimics stretch-induced Cx43 upregulation. Anti-integrin antibodies, RGD peptide treatment, MnCl2 activation, confocal microscopy, immunoblotting in neonatal rat cardiomyocytes under uniaxial stretch Circulation research Medium 15705967
2025 TRPV4 channel activation induces eNOS-mediated NO production and direct S-nitrosylation of Cx43 hemichannels in endothelial cells of resistance arteries, opening Cx43 hemichannels and facilitating Ca2+ influx and endothelial hyperpolarization. TRPV4 and Cx43 are in close proximity (<40 nm) in endothelial cells within lipid rafts; disruption of lipid rafts blunts this signaling. Cx43 hemichannel inhibition impairs TRPV4-induced vasodilatation in vivo. Proximity ligation assay, patch-clamp electrophysiology, Ca2+ imaging, β-cyclodextrin lipid raft disruption, intravital microscopy in mesenteric arterioles, ex vivo myography The Journal of physiology High 39982706
2009 The ODDD-linked dominant Gja1(Jrt) mutation (G60S) acts dominantly on wild-type Cx43 in the myometrium, reducing gap junctional coupling to <15% of wild-type. Phosphorylated Cx43 fails to increase prior to parturition or in response to estrogen in mutant mice, resulting in impaired uterine contraction and prolonged gestation. Patch-clamp electrophysiology, Western blotting, immunostaining, in vitro uterine strip contraction assay Biology of reproduction Medium 19176884
2017 Gja1 acts downstream of Acvr1/cAMP-PKA signaling to regulate uterine decidualization; Gja1 expression is induced by cAMP-PKA pathway (blocked by PKA inhibitor H89); Gja1 in turn regulates Hand2 expression, and Hand2 is required for the stimulatory effects of Gja1 on decidualization markers Prl8a2 and Prl3c1. siRNA knockdown, overexpression, cAMP analog and PKA inhibitor treatments, reporter gene analysis in uterine stromal cells The Journal of endocrinology Medium 28219934
2017 In astrocytes co-expressing Cx43, activated microglia reduce Cx43 expression and astrocyte dye coupling; the degree of intercellular communication in the astroglial network is modulated by microglia activation state. Astrocyte-microglia co-culture, Lucifer Yellow microinjection, immunofluorescence, Western blot Glia Low 12655594
2017 cJun and cFos cooperate to activate Gja1 transcription in Leydig and Sertoli cells via an AP-1 DNA regulatory element located between -132 and -26 bp in the Gja1 promoter; cFos is recruited to this promoter region. Co-transfection of AP-1 expression plasmids with Gja1 promoter/luciferase reporter constructs, site-directed mutation, chromatin immunoprecipitation Gene Medium 28903063
2015 miR-381 indirectly suppresses Cx43 expression by directly targeting the 3'-UTR of C/EBPα; C/EBPα is identified as a transcription factor that binds a canonical element (AATTGTC) at -459/-453 in the Cx43 promoter to activate transcription. Reporter gene assay, site-directed mutation, ChIP, 3'-UTR binding assay Bioscience reports Medium 26450928
2022 GABA, acting through GABAA receptors (not GABAB), induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes, leading to release of glutamate and ATP via Cx43 hemichannels (not pannexin 1 channels); this mechanism was confirmed in hippocampal brain slices. Patch-clamp/hemichannel activity assay, pharmacological receptor blockade (bicuculline, CGP55845, pannexin 1 blocker), Ca2+ imaging in DI NCT1 astrocytes and brain slices International journal of molecular sciences Medium 36362410
2020 Macrophage Cx43 hemichannels mediate ATP efflux; MacΔCx43 macrophages show decreased extracellular ATP and induce decreased cytosolic Ca2+ responses in co-cultured fibroblasts. MacΔCx43 mice have decreased lung fibrosis after bleomycin injury, identifying a Cx43-dependent profibrotic paracrine mechanism from macrophages to fibroblasts via ATP/P2RX4. Macrophage-specific Cx43 conditional KO, ATP efflux measurement, Ca2+ imaging in co-cultured fibroblasts, bleomycin lung injury model Frontiers in immunology Medium 35634278
2020 Cx43 (CX43) in breast cancer MSC-tumor tunneling nanotubes mediates transfer of the metastasis-related protein GIV/CCDC88A from mesenchymal stromal cells to ER+ breast cancer cells that lack GIV, conferring anti-estrogen resistance and enhanced dissemination. Tumor-MSC co-culture, proteome/transcriptome integration, connexin TNT imaging, GIV re-expression functional assays, drug resistance assays The Journal of clinical investigation Medium 39480488
2020 S-nitrosylation of Cx43 by nitric oxide increases phosphorylation at serine 368 (inhibiting gap junction communication) while simultaneously increasing hemichannel open-state probability in myometrial cells, promoting uterine quiescence. Cx43 is downregulated in spontaneous preterm labor myometrium. S-nitrosylation assay, phospho-Cx43 Western blot, hemichannel electrophysiology, pharmacologic inhibition (18β-GA), myometrial contractility assay The Journal of pharmacology and experimental therapeutics Medium 33384302
2002 Cx43 phosphorylation is strongly increased in adherent neurospheres compared to undifferentiated cells, suggesting post-translational regulation during neural progenitor cell differentiation. Cx43 is expressed in undifferentiated neural progenitors and in differentiating astrocytes, the two dye-coupled populations; blockade of gap junctional communication reduces viability of undifferentiated progenitor cells. Western blot (phosphorylation), Lucifer Yellow microinjection, 18β-glycyrrhetinic acid gap junction blockade, viability assay Journal of cell science Low 12140256

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Expression of Cx26, Cx32 and Cx43 gap junction proteins in normal and neoplastic human tissues. International journal of cancer 217 1318266
2014 Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS letters 215 24508467
2009 GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Human mutation 214 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 154 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 116 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
2009 Eps15 interacts with ubiquitinated Cx43 and mediates its internalization. Experimental cell research 100 19835873
2018 Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer letters 93 30472182
2002 Cell coupling and Cx43 expression in embryonic mouse neural progenitor cells. Journal of cell science 90 12140256
2017 GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs. Circulation research 85 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 81 32929449
2004 A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Human mutation 79 14974090
2018 GJA1 (connexin43) is a key regulator of Alzheimer's disease pathogenesis. Acta neuropathologica communications 77 30577786
2002 Cx40 and Cx43 expression ratio influences heteromeric/ heterotypic gap junction channel properties. American journal of physiology. Cell physiology 77 11997262
2021 Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability. The Journal of clinical investigation 74 33621213
2020 Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells. Cancers 74 33003486
2018 Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury. JCI insight 71 30333316
2021 Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway. Frontiers in pharmacology 61 34084134
2017 Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport. Frontiers in physiology 59 29163229
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 58 35312356
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
2013 A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PloS one 55 23951358
2020 Auxiliary trafficking subunit GJA1-20k protects connexin-43 from degradation and limits ventricular arrhythmias. The Journal of clinical investigation 54 32525845
2013 Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system? Frontiers in pharmacology 53 24133447
2003 Cx43 and dual-pathway electrophysiology of the atrioventricular node and atrioventricular nodal reentry. Circulation research 53 12600895
2008 ODDD-linked Cx43 mutants reduce endogenous Cx43 expression and function in osteoblasts and inhibit late stage differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 51 18269311
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 49 36805660
2021 GJA1-20K Enhances Mitochondria Transfer from Astrocytes to Neurons via Cx43-TnTs After Traumatic Brain Injury. Cellular and molecular neurobiology 46 33728536
2005 Matrix-protein-specific regulation of Cx43 expression in cardiac myocytes subjected to mechanical load. Circulation research 45 15705967
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 43 33255329
2018 Altered translation initiation of Gja1 limits gap junction formation during epithelial-mesenchymal transition. Molecular biology of the cell 43 29467255
2015 Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation? Mediators of inflammation 41 26424967
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
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 Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression. Journal of molecular and cellular cardiology 36 29777691
2018 The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer. International journal of molecular sciences 35 29495625
2005 A novel mutation in the GJA1 gene in a family with oculodentodigital dysplasia. Archives of ophthalmology (Chicago, Ill. : 1960) 34 16219735
2022 Cx43-mediated sorting of miRNAs into extracellular vesicles. EMBO reports 33 35593040
2021 Protective mitochondrial fission induced by stress-responsive protein GJA1-20k. eLife 33 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
2018 Cx43 Channel Gating and Permeation: Multiple Phosphorylation-Dependent Roles of the Carboxyl Terminus. International journal of molecular sciences 29 29867029
2021 Importance of Cx43 for Right Ventricular Function. International journal of molecular sciences 28 33498172
2013 Expression of Cx43-related microRNAs in patients with tetralogy of Fallot. World journal of pediatrics : WJP 28 24146179
2003 Altered Cx43 expression during myocardial adaptation to acute and chronic volume overloading. Histology and histopathology 28 12647785
2013 Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. Journal of cell science 27 23606748
2017 Cooperative regulation of Gja1 expression by members of the AP-1 family cJun and cFos in TM3 Leydig and TM4 Sertoli cells. Gene 25 28903063
2009 The anti-arrhythmic peptide AAP10 remodels Cx43 and Cx40 expression and function. Naunyn-Schmiedeberg's archives of pharmacology 25 19326099
2022 Oxidative stress and Cx43-mediated apoptosis are involved in PFOS-induced nephrotoxicity. Toxicology 24 35934180
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
2017 Aberrant Cx43 Expression and Mislocalization in Metastatic Human Melanomas. Journal of Cancer 24 28607585
2017 A novel GJA1 mutation in oculodentodigital dysplasia with extensive loss of enamel. Oral diseases 23 28258662
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
2021 Serine-threonine protein phosphatase regulation of Cx43 dephosphorylation in arrhythmogenic disorders. Cellular signalling 19 34217833
2020 Inhibition of Pyk2 and Src activity improves Cx43 gap junction intercellular communication. Journal of molecular and cellular cardiology 19 32956670
2014 Cx43 phosphorylation on S279/282 and intercellular communication are regulated by IP3/IP3 receptor signaling. Cell communication and signaling : CCS 19 25262337
2020 Involvement of GJA1 and Gap Junctional Intercellular Communication between Cumulus Cells and Oocytes from Women with PCOS. BioMed research international 18 32190671
2020 BTEB2-Activated lncRNA TSPEAR-AS2 Drives GC Progression through Suppressing GJA1 Expression and Upregulating CLDN4 Expression. Molecular therapy. Nucleic acids 18 33294297
2014 Three novel GJA1 missense substitutions resulting in oculo-dento-digital dysplasia (ODDD) - further extension of the mutational spectrum. Gene 18 24508941
2015 To beat or not to beat: degradation of Cx43 imposes the heart rhythm. Biochemical Society transactions 17 26009194
2015 Increased expression of CX43 on stromal cells promotes leukemia apoptosis. Oncotarget 17 26517241
2013 Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer. Cancer cell international 17 23675859
2012 Electrophysiology of single and aggregate Cx43 hemichannels. PloS one 17 23112846
2021 Construction of a lncRNA/pseudogene-hsa-miR-30d-5p-GJA1 regulatory network related to metastasis of pancreatic cancer. Genomics 16 33839271
2020 Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes. Biomolecules 16 33066499
2010 Novel mutations in the connexin43 (GJA1) and GJA1 pseudogene may contribute to nonsyndromic hearing loss. Human genetics 16 20130915
2024 Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels. The Journal of clinical investigation 15 39480488
2022 Upregulated miR-206 Aggravates Deep Vein Thrombosis by Regulating GJA1-Mediated Autophagy of Endothelial Progenitor Cells. Cardiovascular therapeutics 15 35360546
2022 Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury. Frontiers in immunology 15 35634278
2022 GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels. International journal of molecular sciences 15 36362410
2020 Novel Tocolytic Strategy: Modulating Cx43 Activity by S-Nitrosation. The Journal of pharmacology and experimental therapeutics 15 33384302
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
2022 GJA1-20k and Mitochondrial Dynamics. Frontiers in physiology 14 35399255
2015 A novel truncation mutation in GJA1 associated with open angle glaucoma and microcornea in a large Chinese family. Eye (London, England) 14 25976645
2014 Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac. Molecular medicine reports 14 24714982
2024 Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage. Biological research 13 38576018
2024 Chlorpromazine overcomes temozolomide resistance in glioblastoma by inhibiting Cx43 and essential DNA repair pathways. Journal of translational medicine 13 39026284
2020 β2-Adrenergic Receptor Stimulation Upregulates Cx43 Expression on Glioblastoma Multiforme and Olfactory Ensheathing Cells. Journal of molecular neuroscience : MN 13 32506304
2015 Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients. The Biochemical journal 13 26349540
2022 GJA1 reverses arsenic-induced EMT via modulating MAPK/ERK signaling pathway. Toxicology and applied pharmacology 12 35750204
2022 Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization. Frontiers in endocrinology 12 36120455
2019 Down-regulation of Cx43 expression on PIH-HUVEC cells attenuates monocyte-endothelial adhesion. Thrombosis research 12 31112837
2017 Gja1 acts downstream of Acvr1 to regulate uterine decidualization via Hand2 in mice. The Journal of endocrinology 12 28219934
2014 A micropatterning approach for imaging dynamic Cx43 trafficking to cell-cell borders. FEBS letters 12 24444605
2025 Endothelial TRPV4-Cx43 signalling complex regulates vasomotor tone in resistance arteries. The Journal of physiology 11 39982706
2024 CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling. Stem cell research & therapy 11 39623456

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