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Gene Review

GJA5  -  gap junction protein, alpha 5, 40kDa

Homo sapiens

Synonyms: ATFB11, CX40, Connexin-40, Cx40, Gap junction alpha-5 protein
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Disease relevance of GJA5

  • In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF [1].
  • A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described [1].
  • Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia [2].
  • No mRNA expression of Cx37, Cx40 or Cx45 in either mesothelioma tumour cells or the primary mesothelial cells was detected [3].
  • METHODS: A communication-deficient human hepatoma cell line (SKHep1) was stably transfected with human Cx40 cDNA and the properties of Cx40 gap junctions channels and their modulation by cAMP were analyzed using immunocytochemistry, Western blotting, dual patch clamp, and dye coupling [4].

High impact information on GJA5

  • Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy [5].
  • Microinjection of Cx40 cRNA into Xenopus oocytes induced functional cell-to-cell channels between pairs [6].
  • Based on both protein and nucleotide sequence, mouse Cx40 is more closely related to mouse Cx43 (alpha subgroup of connexins) than to mouse Cx32 (beta subgroup) [6].
  • Transfection of mouse Cx40 DNA, under control of the SV-40 early promoter, into coupling-deficient human HeLa or SK-Hep-1 cells resulted in expression of the expected transcript and restoration of fluorescent dye transfer in transfected clones [6].
  • The coding region of Cx40 is uninterrupted by introns and is detected as a single copy gene in the mouse genome [6].

Biological context of GJA5


Anatomical context of GJA5


Associations of GJA5 with chemical compounds

  • Stimulation in vitro of T and B lymphocytes with phytohaemagglutinin (PHA) and lipopolysaccharide (LPS), respectively, increased Cx40 and Cx43 protein expression [14].
  • Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil [1].
  • When cytotrophoblastic cells were cultured on Matrigel for 2 days, alpha5beta1 integrin expression was observed concomitant with the presence of Cx40 mRNA and of Cx40 protein between the cells [15].
  • Affinity purification of material solubilized by Triton X-100 from cells co-expressing mutant Cx43 or mutant Cx40 with wild-type Cx40, Cx43 or Cx26 showed that introducing the mutations did not affect the compatibility or incompatibility of these proteins for heteromeric mixing [16].
  • Unlike wild-type Cx40, Cx40E12S,E13G channels were insensitive to block by 2 mM spermine [16].

Regulatory relationships of GJA5


Other interactions of GJA5

  • Immunostaining revealed typical punctate staining for Cx43 and Cx40 along regions of intimate cell-to-cell contact between hMSCs [18].
  • Cx45 was detectable only at very low levels, with a trend toward higher levels in the atria than the ventricles in a pattern similar to Cx40 [13].
  • Under control conditions, Cx43, Cx40, and Cx37 protein and mRNA were present in HUVEC [19].
  • Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms [2].
  • If TNF-alpha was removed from the medium, Cx37 and Cx40 expression was restored within 24 h [19].

Analytical, diagnostic and therapeutic context of GJA5


  1. Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. Dhein, S., Polontchouk, L., Salameh, A., Haefliger, J.A. Biol. Cell (2002) [Pubmed]
  2. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Makita, N., Sasaki, K., Groenewegen, W.A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. Heart rhythm : the official journal of the Heart Rhythm Society. (2005) [Pubmed]
  3. Expression of cell adhesion molecules and connexins in gap junctional intercellular communication deficient human mesothelioma tumour cell lines and communication competent primary mesothelial cells. Pelin, K., Hirvonen, A., Linnainmaa, K. Carcinogenesis (1994) [Pubmed]
  4. Human connexin40 gap junction channels are modulated by cAMP. van Rijen, H.V., van Veen, T.A., Hermans, M.M., Jongsma, H.J. Cardiovasc. Res. (2000) [Pubmed]
  5. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Kass, S., MacRae, C., Graber, H.L., Sparks, E.A., McNamara, D., Boudoulas, H., Basson, C.T., Baker, P.B., Cody, R.J., Fishman, M.C. Nat. Genet. (1994) [Pubmed]
  6. Molecular cloning and functional expression of mouse connexin40, a second gap junction gene preferentially expressed in lung. Hennemann, H., Suchyna, T., Lichtenberg-Fraté, H., Jungbluth, S., Dahl, E., Schwarz, J., Nicholson, B.J., Willecke, K. J. Cell Biol. (1992) [Pubmed]
  7. Physical mapping of the human connexin 40 (GJA5), flavin-containing monooxygenase 5, and natriuretic peptide receptor a genes on 1q21. Gelb, B.D., Zhang, J., Cotter, P.D., Gershin, I.F., Desnick, R.J. Genomics (1997) [Pubmed]
  8. Gap junctions are required for trophoblast proliferation in early human placental development. Nishimura, T., Dunk, C., Lu, Y., Feng, X., Gellhaus, A., Winterhager, E., Rossant, J., Lye, S.J. Placenta (2004) [Pubmed]
  9. Cx40 polymorphism in human atrial fibrillation. Hauer, R.N., Groenewegen, W.A., Firouzi, M., Ramanna, H., Jongsma, H.J. Advances in cardiology. (2006) [Pubmed]
  10. Contribution of connexins to the function of the vascular wall. Haefliger, J.A., Nicod, P., Meda, P. Cardiovasc. Res. (2004) [Pubmed]
  11. Molecular cloning of two human cardiac gap junction proteins, connexin40 and connexin45. Kanter, H.L., Saffitz, J.E., Beyer, E.C. J. Mol. Cell. Cardiol. (1994) [Pubmed]
  12. Expression of multiple gap junction proteins in human fetal and infant hearts. Chen, S.C., Davis, L.M., Westphale, E.M., Beyer, E.C., Saffitz, J.E. Pediatr. Res. (1994) [Pubmed]
  13. Chamber-related differences in connexin expression in the human heart. Vozzi, C., Dupont, E., Coppen, S.R., Yeh, H.I., Severs, N.J. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  14. Intercellular communication in the immune system: differential expression of connexin40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations. Oviedo-Orta, E., Hoy, T., Evans, W.H. Immunology (2000) [Pubmed]
  15. Connexin expression and gap junctional intercellular communication in human first trimester trophoblast. Cronier, L., Defamie, N., Dupays, L., Théveniau-Ruissy, M., Goffin, F., Pointis, G., Malassiné, A. Mol. Hum. Reprod. (2002) [Pubmed]
  16. N-terminal residues in Cx43 and Cx40 determine physiological properties of gap junction channels, but do not influence heteromeric assembly with each other or with Cx26. Gemel, J., Lin, X., Veenstra, R.D., Beyer, E.C. J. Cell. Sci. (2006) [Pubmed]
  17. EGF Modulates Trophoblast Migration through Regulation of Connexin 40. Wright, J.K., Dunk, C.E., Perkins, J.E., Winterhager, E., Kingdom, J.C., Lye, S.J. Placenta (2006) [Pubmed]
  18. Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. Valiunas, V., Doronin, S., Valiuniene, L., Potapova, I., Zuckerman, J., Walcott, B., Robinson, R.B., Rosen, M.R., Brink, P.R., Cohen, I.S. J. Physiol. (Lond.) (2004) [Pubmed]
  19. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. van Rijen, H.V., van Kempen, M.J., Postma, S., Jongsma, H.J. Cytokine (1998) [Pubmed]
  20. Gap junctions and connexon hemichannels in human embryonic stem cells. Huettner, J.E., Lu, A., Qu, Y., Wu, Y., Kim, M., McDonald, J.W. Stem Cells (2006) [Pubmed]
  21. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Christiansen, J., Dyck, J.D., Elyas, B.G., Lilley, M., Bamforth, J.S., Hicks, M., Sprysak, K.A., Tomaszewski, R., Haase, S.M., Vicen-Wyhony, L.M., Somerville, M.J. Circ. Res. (2004) [Pubmed]
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