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Gene Review

Gja3  -  gap junction protein, alpha 3

Mus musculus

Synonyms: Cnx46, Connexin-46, Cx43, Cx46, Gap junction alpha-3 protein, ...
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Disease relevance of Gja3

  • Targeted null mutations in Gja8 and Gja3 in mice cause cataracts with recessive inheritance [1].
  • The objective of this study was to evaluate the effectiveness of combination therapy of Cx43-expressing plasmid DNA (pCMV-Cx43) and DTX both in vitro and in vivo using a non-viral vector in human prostate cancer PC-3 cells [2].
  • Surprisingly, in lung adenomas Cx32 and Cx43 expressions were not detected, although the expression of connexins 26 and 46 was present [3].
  • Thus, the morphological heart abnormalities of Cx43 null mice are most likely not caused by lack of Cx43 in neural crest cells [4].
  • Our cDNA microarray analysis of normal and nitrofen-exposed neonatal mice with hypoplastic lungs, associated congenital diaphragmatic hernia (CDH) and heart developmental defects showed up-regulation of Cx43 [5].

High impact information on Gja3

  • Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed [6].
  • Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases [6].
  • In addition, double heterozygous knockout lenses retained normal growth and clarity, whereas knockover lenses, where native Cx46 was deleted and homozygously knocked into the Cx50 locus, displayed significantly deficient growth but maintained clarity [7].
  • By mating knockin and knockout mice, we show that heterozygous replacement of Cx50 with Cx46 rescued growth but produced dominant cataracts that resulted from disruption of lens fiber morphology and crystallin precipitation [7].
  • Expression of connexin 43 (Cx43) is critical for normal hematopoiesis [8].

Chemical compound and disease context of Gja3

  • We have previously discovered that overexpression of connexin43 (Cx43) in C6 glioma cells not only reduces proliferation but also leads to production of soluble growth-inhibitory factors [9].

Biological context of Gja3

  • A functional impairment of endogenous alpha 3 connexin is therefore partly responsible for cellular phenotypes in the Lop10 mice [1].
  • Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown [10].
  • The analysis revealed that no gene cohort sharing either primary function or chromosomal location was significantly altered (up-and down-regulation were roughly balanced) in Cx43(-/-) brains, but each cohort exhibited significant perturbation of transcript abundance proportions and reduced expression variability and coordination [11].
  • Forced expression of Cx43 in the cells induced apoptotic cells by down-regulation of Bcl-2 expression and significantly more up-regulation of caspase-3 activity than either treatment alone [2].
  • Transfection of pCMV-Cx43 into the cells neither inhibited tumor growth nor increased gap junctional intercellular communication; however, combination therapy of pCMV-Cx43 and DTX significantly inhibited cell growth [2].

Anatomical context of Gja3

  • Gap junctions in rodent lens fibers contain two known intercellular channel-forming proteins, connexin50 (Cx50) and Cx46 [12].
  • In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH [10].
  • Only Cx43 was expressed from neural crest cells onwards [13].
  • In mature myelin-forming Schwann cells, expression of multiple connexins, i.e. connexin (Cx) 43, Cx29, Cx32, and Cx46 (after nerve injury) has been detected [13].
  • Transgenic mice with conditional deletion of Cx43 in smooth muscle cells (SMC) were generated [14].

Associations of Gja3 with chemical compounds


Physical interactions of Gja3

  • A G22R point mutation in alpha8 connexin (Cx50) has been previously shown to cause a severe cataract by interacting with endogenous wild-type alpha3 connexin (Cx46) in mouse lenses [19].

Other interactions of Gja3

  • Freeze-fracture and fracture labeling revealed that the junctional assembly, packing organization and topographic interactions between connexons and MP26 differed when Cx46 and Cx50 were co-assembled in the wild-type or expressed separately in the two distinct knockout phenotypes [15].
  • The role of Cx26 and Cx46 is yet to be determined [3].
  • Connexin alpha 3 (Cx46 or Gja3) gene targeted null mice developed lens nuclear cataracts shortly after birth [20].
  • The residual 5% coupling contributed by the additional connexins (Cx40, Cx45, and Cx46) expressed in KO astrocytes still suffices to provide a more substantial portion of Ca2+ wave propagation than does signaling through extracellular purinergic pathways [21].

Analytical, diagnostic and therapeutic context of Gja3

  • Our previously reported cDNA array datasets from neonatal wild-type and Cx43(-/-) (approved gene symbol Gja1) mouse brains were further analyzed to identify underlying interlinkages in the brain transcriptome [11].
  • Measurements of gastrointestinal transit and of the visceromotor response by utilizing a standardized colorectal distension model to quantify alterations of visceral sensory function were also performed in SMC-specific Cx43 null mice and control littermates [14].
  • The combination of repeated intratumoral injection of pCMV-Cx43 (10 microg/tumor) with non-viral vector and a single intravenous injection of DTX (15 mg/kg) was compared with a repeated injection of Cx43 alone and a single injection of DTX alone on PC-3 tumor xenografts [2].
  • Cx43 was similarly detectable in normal lung, smaller size tumor and larger size tumor, but western blotting showed that Cx43 was phosphorylated during lung tumorigenesis [22].
  • Using specific site-directed mutagenesis in the third membrane-spanning (3M) domain of connexin43 (Cx43), we abolished the intrinsic gap junction intercellular communication (GJIC) in BC31 cells either by closing the gap junctional channels or by disruption of the transport of connexin complexes to the lateral membrane [23].


  1. A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice. Chang, B., Wang, X., Hawes, N.L., Ojakian, R., Davisson, M.T., Lo, W.K., Gong, X. Hum. Mol. Genet. (2002) [Pubmed]
  2. Combination of non-viral connexin 43 gene therapy and docetaxel inhibits the growth of human prostate cancer in mice. Fukushima, M., Hattori, Y., Yoshizawa, T., Maitani, Y. Int. J. Oncol. (2007) [Pubmed]
  3. Altered expression of connexins in urethane-induced mouse lung adenomas. Avanzo, J.L., Mesnil, M., Hernandez-Blazquez, F.J., da Silva, T.C., Fukumasu, H., Mori, C.M., Yamasaki, H., Dagli, M.L. Life Sci. (2006) [Pubmed]
  4. Normal embryonic development and cardiac morphogenesis in mice with Wnt1-Cre-mediated deletion of connexin43. Kretz, M., Eckardt, D., Krüger, O., Kim, J.S., Maurer, J., Theis, M., van Rijen, H.V., Schorle, H., Willecke, K. Genesis (2006) [Pubmed]
  5. Connexin 43 gene expression in mice with cardiopulmonary developmental defects. Le, M., Li, Z., Cilley, R.E., Donahue, H., Chinoy, M.R. Front. Biosci. (2006) [Pubmed]
  6. Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries. Parthasarathi, K., Ichimura, H., Monma, E., Lindert, J., Quadri, S., Issekutz, A., Bhattacharya, J. J. Clin. Invest. (2006) [Pubmed]
  7. Dominant cataracts result from incongruous mixing of wild-type lens connexins. Martinez-Wittinghan, F.J., Sellitto, C., Li, L., Gong, X., Brink, P.R., Mathias, R.T., White, T.W. J. Cell Biol. (2003) [Pubmed]
  8. Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Montecino-Rodriguez, E., Leathers, H., Dorshkind, K. Blood (2000) [Pubmed]
  9. CCN3 (NOV) interacts with connexin43 in C6 glioma cells: possible mechanism of connexin-mediated growth suppression. Fu, C.T., Bechberger, J.F., Ozog, M.A., Perbal, B., Naus, C.C. J. Biol. Chem. (2004) [Pubmed]
  10. Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. Chung, D.J., Castro, C.H., Watkins, M., Stains, J.P., Chung, M.Y., Szejnfeld, V.L., Willecke, K., Theis, M., Civitelli, R. J. Cell. Sci. (2006) [Pubmed]
  11. Connexin43 and the brain transcriptome of newborn mice. Iacobas, D.A., Iacobas, S., Spray, D.C. Genomics (2007) [Pubmed]
  12. Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. White, T.W., Goodenough, D.A., Paul, D.L. J. Cell Biol. (1998) [Pubmed]
  13. Analysis of connexin expression during mouse Schwann cell development identifies connexin29 as a novel marker for the transition of neural crest to precursor cells. Li, J., Habbes, H.W., Eiberger, J., Willecke, K., Dermietzel, R., Meier, C. Glia (2007) [Pubmed]
  14. Ablation of connexin43 in smooth muscle cells of the mouse intestine: functional insights into physiology and morphology. D??ring, B., Pfitzer, G., Adam, B., Liebregts, T., Eckardt, D., Holtmann, G., Hofmann, F., Feil, S., Feil, R., Willecke, K. Cell Tissue Res. (2007) [Pubmed]
  15. Structural and immunocytochemical alterations in eye lens fiber cells from Cx46 and Cx50 knockout mice. Dunia, I., Cibert, C., Gong, X., Xia, C.H., Recouvreur, M., Levy, E., Kumar, N., Bloemendal, H., Benedetti, E.L. Eur. J. Cell Biol. (2006) [Pubmed]
  16. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Heusch, G., Büchert, A., Feldhaus, S., Schulz, R. Basic Res. Cardiol. (2006) [Pubmed]
  17. Exchange of gating properties between rat cx46 and chicken cx45.6. Tong, J.J., Liu, X., Dong, L., Ebihara, L. Biophys. J. (2004) [Pubmed]
  18. Nonylphenol alters connexin 43 levels and connexin 43 phosphorylation via an inhibition of the p38-mitogen-activated protein kinase pathway. Aravindakshan, J., Cyr, D.G. Biol. Reprod. (2005) [Pubmed]
  19. Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation. Xia, C.H., Cheung, D., DeRosa, A.M., Chang, B., Lo, W.K., White, T.W., Gong, X. J. Cell. Sci. (2006) [Pubmed]
  20. Genetic factors influence cataract formation in alpha 3 connexin knockout mice. Gong, X., Agopian, K., Kumar, N.M., Gilula, N.B. Dev. Genet. (1999) [Pubmed]
  21. Calcium waves between astrocytes from Cx43 knockout mice. Scemes, E., Dermietzel, R., Spray, D.C. Glia (1998) [Pubmed]
  22. Connexin expression in mouse lung tumor. Udaka, N., Miyagi, Y., Ito, T. Cancer Lett. (2007) [Pubmed]
  23. Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo. Krutovskikh, V.A., Troyanovsky, S.M., Piccoli, C., Tsuda, H., Asamoto, M., Yamasaki, H. Oncogene (2000) [Pubmed]
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