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Gene Review

GJA1  -  gap junction protein, alpha 1, 43kDa

Canis lupus familiaris

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Disease relevance of GJA1


High impact information on GJA1

  • Chronic AF increased the expression and distribution of gap junction protein Cx43, which became reduced in ablated and nearby nonablated areas [2].
  • At the interface with the underlying necrotic cells, the EBZ myocardium showed a marked disruption of gap-junctional distribution, with Cx43 labeling abnormally arrayed longitudinally along the lateral surfaces of the cells [5].
  • Chronic rapid atrial pacing (group 2) increased the expression of Cx43, which was absent in ablated areas and markedly depressed in viable atrial myocytes near the ablation zones (group 1) [2].
  • METHODS AND RESULTS: The EBZ overlying 4-day-old anterior infarcts in three dogs with inducible VT and three noninducible dogs was mapped with a high-resolution electrode array and systematically examined by standard histology and confocal immunolocalization of Cx43 [5].
  • BACKGROUND: We assessed the effects of radiofrequency catheter ablation (RFCA) of the atrial epicardium on pacing-induced sustained atrial fibrillation (AF) and the expression and distribution of the intercellular gap junction protein connexin 43 (Cx43) in dogs [2].

Biological context of GJA1

  • To determine whether heterogeneous Cx43 expression influenced EP function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure transmural conduction velocity (thetaTM), dV/dt(max), transmural space constant (lambdaTM), and transmural gradients of action potential duration (APD) [6].
  • We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43) [7].
  • CONCLUSIONS: AV junctional cells around both annuli are histologically similar to atrial cells but resemble nodal cells in their cellular electrophysiology, response to adenosine, and lack of connexin-43 [8].
  • The objectives of the present study were to determine whether Cx43 is expressed by sinus node myocytes, to characterize the spectrum of connexin expression phenotypes in sinus node pacemaker cells, and to define the spatial distribution of different connexin phenotypes in the intact sinus node [9].
  • These results suggest that second messenger pathways involving protein kinase C, but not cAMP- or cGMP-dependent protein kinase, led to changes in electrophoretic mobility of Cx43, revealed by Western blot, consistent with an alteration in the state of phosphorylation of the gap junction protein [10].

Anatomical context of GJA1

  • Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial theta(TM) (by 12 +/- 10%) and lambda(TM) (by 13 +/- 7%), compared with deeper transmural layers (P < 0.05) [7].
  • A similar colocalization pattern was observed for the Cx43deltaI382 and Cx43 delta378-382 mutants, which were translocated to the plasma membrane and formed functional gap junction channels [11].
  • The C-terminus of Cx43 has been shown to interact with the PDZ2 domain of the tight and adherens junction associated zona occludens 1 (ZO-1) protein [11].
  • Although the major cardiac gap junction protein, connexin43 (Cx43), is expressed abundantly in atrial and ventricular muscle, its expression in the sinus node has been a subject of controversy [9].
  • Quantitative in situ hybridization demonstrated a modest but not statistically significant increase in Cx43 mRNA in Purkinje fibers compared with ventricular myocardium [12].

Associations of GJA1 with chemical compounds


Analytical, diagnostic and therapeutic context of GJA1

  • Relative Cx43 expression, quantified by confocal immunofluorescence, was significantly lower (by 24 +/- 17%; P < 0.05) in subepicardial compared with deeper layers [6].
  • The hypothesis that an altered expression of gap junction (GJ) proteins, connexin37 (Cx37), Cx40 and Cx43 will contribute to adaptive arteriogenesis was tested in growing coronary collateral vessels (CV) of the dog heart by immunoconfocal microscopy and transmission electron microscopy (TEM) [16].
  • Western blots of total cell homogenates showed that the dephosphorylated form of Cx43 was more abundant than the phosphorylated forms [10].
  • Cx43 distribution was visualized by confocal microscopy [3].
  • Connexin 43 becomes hypophosphorylated after treatment with 1% DMN for 15 minutes, but this hypophosphorylation is inhibited by pretreatment with dibutyryl-cAMP [15].


  1. Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. Akar, F.G., Spragg, D.D., Tunin, R.S., Kass, D.A., Tomaselli, G.F. Circ. Res. (2004) [Pubmed]
  2. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Elvan, A., Huang, X.D., Pressler, M.L., Zipes, D.P. Circulation (1997) [Pubmed]
  3. Heterogeneous loss of connexin43 protein in ischemic dog hearts. Huang, X.D., Sandusky, G.E., Zipes, D.P. J. Cardiovasc. Electrophysiol. (1999) [Pubmed]
  4. Gap junction intercellular communication in gliomas is inversely related to cell motility. McDonough, W.S., Johansson, A., Joffee, H., Giese, A., Berens, M.E. Int. J. Dev. Neurosci. (1999) [Pubmed]
  5. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Peters, N.S., Coromilas, J., Severs, N.J., Wit, A.L. Circulation (1997) [Pubmed]
  6. Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. Poelzing, S., Akar, F.G., Baron, E., Rosenbaum, D.S. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  7. Altered connexin43 expression produces arrhythmia substrate in heart failure. Poelzing, S., Rosenbaum, D.S. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  8. Atrioventricular junctional tissue. Discrepancy between histological and electrophysiological characteristics. McGuire, M.A., de Bakker, J.M., Vermeulen, J.T., Moorman, A.F., Loh, P., Thibault, B., Vermeulen, J.L., Becker, A.E., Janse, M.J. Circulation (1996) [Pubmed]
  9. Differential expression of gap junction proteins in the canine sinus node. Kwong, K.F., Schuessler, R.B., Green, K.G., Laing, J.G., Beyer, E.C., Boineau, J.P., Saffitz, J.E. Circ. Res. (1998) [Pubmed]
  10. Connexin43 in MDCK cells: regulation by a tumor-promoting phorbol ester and Ca2+. Berthoud, V.M., Ledbetter, M.L., Hertzberg, E.L., Sáez, J.C. Eur. J. Cell Biol. (1992) [Pubmed]
  11. Connexin43 PDZ2 binding domain mutants create functional gap junctions and exhibit altered phosphorylation. Jin, C., Martyn, K.D., Kurata, W.E., Warn-Cramer, B.J., Lau, A.F. Cell Commun. Adhes. (2004) [Pubmed]
  12. Distinct patterns of connexin expression in canine Purkinje fibers and ventricular muscle. Kanter, H.L., Laing, J.G., Beau, S.L., Beyer, E.C., Saffitz, J.E. Circ. Res. (1993) [Pubmed]
  13. Caveolae from canine airway smooth muscle contain the necessary components for a role in Ca(2+) handling. Darby, P.J., Kwan, C.Y., Daniel, E.E. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) [Pubmed]
  14. The preventive effect of green tea on the gap junction intercellular communication in renal epithelial cells treated with a renal carcinogen. Takahashi, H., Nomata, K., Mori, K., Matsuo, M., Miyaguchi, T., Noguchi, M., Kanetake, H. Anticancer Res. (2004) [Pubmed]
  15. Restoration of gap junctional intercellular communication by dibutyryl-cAMP in renal epithelial cells treated with renal carcinogen. Sato, H., Nomata, K., Noguchi, M., Takahashi, H., Watanabe, J., Kanetake, H. Anticancer Res. (2003) [Pubmed]
  16. Connexin37, not Cx40 and Cx43, is induced in vascular smooth muscle cells during coronary arteriogenesis. Cai, W.J., Koltai, S., Kocsis, E., Scholz, D., Schaper, W., Schaper, J. J. Mol. Cell. Cardiol. (2001) [Pubmed]
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