Disease relevance of Gja1

• Reversible connexin 43 dephosphorylation during hypoxia and reoxygenation is linked to cellular ATP levels [1].
• Dephosphorylation of Cx43 and uncoupling of gap junctions occur during ischemia, but the significance of Cx43 phosphorylation in this setting is unknown [1].
• Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells [2].
• Detection of a novel pattern of connexin 43 immunoreactivity responsive to dehydration in rat hypothalamic magnocellular nuclei [3].
• Neonatal hypothyroidism alters the localization of gap junctional protein connexin 43 in the testis and messenger RNA levels in the epididymis of the rat [4].

Psychiatry related information on Gja1

• In the CN, however, Cx43 density was both increased with Huntington's disease and became located in patches [5].
• The cardiomyocyte sheets became attached to the infarcted myocardium, showed angiogenesis, expressed connexin-43, and appeared as homogeneous tissue in the myocardium Electrophysiological experiments showed a QRS complex with one peak in the treated scar area in the T group, but two peaks, indicative of branch block, in that of the other groups [6].

High impact information on Gja1

• We have used sucrose gradient fractionation and chemical cross-linking to study the first step in gap junction assembly, oligomerization of Cx43 monomers into connexon channels [7].
• In contrast with other plasma membrane proteins, multisubunit assembly of Cx43 was specifically and completely blocked when endoplasmic reticulum (ER)-to-Golgi transport was inhibited by 15 degrees C incubation, carbonyl cyanide m-chloro-phenylhydrazone, or brefeldin A or in CHO cell mutants with temperature-sensitive defects in secretion [7].
• Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases [8].
• Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries [8].
• At the long-term level, vitamin D(3) , lipopolysaccharide, thyroid hormone T(3), dexamethasone, platelet-derived growth factor, endothelin 1, and interleukin 1beta up-regulate connexin 43 protein and messenger RNA expression and enhance intercellular communication [9].

Chemical compound and disease context of Gja1

• Cx43 became profoundly dephosphorylated during hypoxia only when glucose supplies were limited and was completely rephosphorylated within 30 minutes of reoxygenation [1].
• The objectives of this study were to determine the effects of propylthiouracil (PTU)-induced neonatal hypothyroidism on the gap junctional protein Cx43 in rat testis and epididymis [4].
• This novel form of longitudinally arranged Cx 43 immunoreactivity was modified by dehydration and halothane exposure, but not lactation [3].
• The objective of the present study was to examine the effects of the antiprogesterone RU486 on the expression levels of multiple gap junction (GJ) gene products and, in detail, on alpha 1 (connexin43 [Cx43]), in various regions of the rat implantation chamber during experimentally induced preterm labor at mid/late stages of gestation [10].
• Geldanamycin abolished the 2-fold increase in mitochondrial Cx43 induced by 2 preconditioning cycles of ischemia/reperfusion, but this effect was not associated with reduced protection [11].

Biological context of Gja1

• ERK activation resulted in phosphorylation at Ser-279 and Ser-282 of the gap junctional protein, connexin-43, known to result in the loss of gap junctional intercellular communication [12].
• Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells [13].
• Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner [14].
• In the present work, we analyzed the ability of polarized FRT cells (that are gap junction deficient) to form follicle-like structures after stable transfection with either Cx32 or Cx43 genes [15].
• However, although the Cx-43 gene has been reported to be responsive to estrogen, it does not contain a palindromic estrogen response element [16].

Anatomical context of Gja1

• 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 [8].
• Labor was also associated with a coincident expression of c-fos and Cx-43 in the myometrium, although there was no change in c-jun mRNA levels during this period [16].
• In the present study we have investigated effects of FGF-2 and of other growth factors on the expression and function of cx43 in astroglial cells cultured from telencephalic cortex, striatum, and mesencephalon of newborn rats [17].
• As thyrocytes cultured in the form of a monolayer only express Cx43, we hypothesized that Cx32 could play a role in thyroid folliculogenesis [15].
• Long-term up-regulation of Cx43 in reactive astrocytes may be one critical component in the rearrangement of the local astroglial network following SCI [18].

Associations of Gja1 with chemical compounds

• Epidermal growth factor receptor is a common mediator of quinone-induced signaling leading to phosphorylation of connexin-43: role of glutathione and tyrosine phosphatases [12].
• These results indicate that high glucose concentrations inhibited GJIC activity by reducing Cx43 synthesis in RME cells [13].
• Since essentially all of the Cx43 in G0 cells is assembled into Triton X-100-resistant junctions, Cx43-ZO-1 interaction may contribute to their stability [14].
• Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP [19].
• These data support our hypothesis that estrogen (and, by extension, labor-)-induced increases in Cx-43 mRNA are mediated indirectly through newly synthesized trans-activating factors [16].

Physical interactions of Gja1

• Far Western analysis revealed that ZO-2 can directly bind to Cx43 independent of other interacting partners [14].
• Immunoblot analysis of associated proteins showed that the C-terminal domain of connexin-43 binds to the N-terminal domain of ZO-1 [20].
• Similarly, antibody against Cx40 coimmunoprecipitated Cx43 from the same connexon fraction but only Cx40 from Cx (monomer) fractions [21].

Enzymatic interactions of Gja1

• In addition, studies with rat primary-cultured cardiomyocytes demonstrated that acetylcholine effectively prevented the hypoxia-induced loss of phosphorylated Cx43 and ameliorated the loss of cell-to-cell communication as determined by Lucifer Yellow dye transfer assay, which supports the in vivo results [22].

Co-localisations of Gja1

• However, localization of connexin-43 likely involves an interaction with the cytoskeleton; immunofluorescence microscopy showed that in cardiac myocytes, connexin-43 specifically colocalizes with the cytoskeletal proteins ZO-1 and alpha-spectrin [20].

Regulatory relationships of Gja1

• Moreover, in the same brain regions Cx32 and Cx43 were up-regulated in non-neruronal cells whereas the neuronal Cx36 was down-regulated [23].
• AT-II-induced Cx43 induction could be completely inhibited by the AT1 receptor antagonist losartan [24].
• We show herein that phagocytosis activation by LPS concomitantly stimulated Cx33 and inhibited Cx43 mRNA levels [25].
• Stretch-induced upregulation of Cx43 expression was blocked by either anti-VEGF antibody or anti-TGF-beta antibody [26].
• These findings indicate that alterations in Cx32 and Cx26 expression occur rapidly in hepatocytes stimulated to proliferate and that several nonparenchymal liver cell types upregulate Cx43 expression when induced to proliferate [27].

Other interactions of Gja1

• Instead, Cx32 and Cx43 were restricted to glial gap junctions [28].
• Among at least six gap junction-forming connexin proteins in adult rat brain, connexin- (Cx) 32, Cx36, and Cx43 have been reported to occur in neurons [28].
• MS/MS analysis of tryptic fragments yielded several proteins including zona occludens-1 (ZO-1), a structural protein previously identified to interact with Cx43, and ZO-2, a potential novel interacting partner [14].
• We confirmed the interaction of ZO-2 with Cx43 by using a combination of fusion protein "pull down," co-immunoprecipitation, and co-localization experiments [14].
• Treatment of pregnant rats with progesterone beginning on day 20 (which blocks both the increase in Cx-43 expression and the onset of labor) maintained the elevated expression of Cx-26 [29].

Analytical, diagnostic and therapeutic context of Gja1

• Using alkaline phosphatase and Western blot analyses, we identified three forms of Cx43: a nonphosphorylated form (P0) and two phosphorylated forms (P1 and P2) [13].
• Using immunofluorescence microscopy, we observed Cx43 localization at specific sites of contact (plaques) between adjacent cells [13].
• We have utilized tandem mass spectrometry (MS/MS) sequence analysis as a screen to identify proteins from cell lysates that interact with the C-terminal cytoplasmic region of connexin 43 (Cx43) [14].
• These associative data were strengthened by our observation that in paradigms in which labor was induced prematurely by ovariectomy or blocked by treatment with progesterone, changes in c-fos expression were closely matched by changes in Cx-43 mRNA [16].
• Decreases in steady-state connexin 43 mRNA levels were detected by northern blot analysis within 1 h and paralleled changes in steady-state beta-actin mRNA, but these changes did not occur rapidly enough to account for the rapid loss of gap-junction function [30].

References