Disease relevance of GJA1

• Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression [1].
• Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF [1].
• Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs [2].
• Cx43 dephosphorylation occurred within 1 hour following ischemia [3].
• In addition, glioma cells were stimulated to migrate in a dose-dependant manner in response to epidermal growth factor (EGF) coincident with the reduction of Cx43 levels and increased serine phosphorylation [4].

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

• The C-terminal tail of Cx43 is important for regulation of gap junctions via phosphorylation of specific tyrosine and serine residues and through interactions with cellular proteins [11].
• Also, the PM Ca(2+) pump was present but not connexin 43 (a noncaveolae PM protein), the sarcoplasmic reticulum (SR) Ca(2+) pump, or the type 1 inositol 1,4, 5-trisphosphate receptor, supporting the idea that SR-derived membranes were not present [13].
• Phosphorylation of Cx43 was not significantly affected by 8-Bromo-cAMP or 8-Bromo-cGMP [10].
• The levels of GJIC and Cx 43 expression were markedly decreased in MDCK cells exposed to dimethylnitrosamine [14].
• In this study, we examined gap junctional intercellular communication and connexin 43 expression in renal epithelial cells treated with 1% DMN and also examined the effects of dibutyryl-cAMP on preventing gap junctional disturbances [15].

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].

References