Abstract
ABSTRACTConnexins have been proposed as a target for therapeutic treatment of a variety of conditions. The main approaches have been by antisense or small peptides specific against connexins. Some of these peptides enhance communication while others interfere with connexin binding partners or bind to the intracellular and extracellular loops of connexins. Here, we explored the mechanism of action of a connexin mimetic peptide by evaluating its effect on gap junction channels, connexin protein levels and hemichannel activity in fibroblast cells under normal conditions and following ischemia reperfusion injury which elevates Cx43 levels, increases hemichannel activity and causes cell death. Our results showed that the effects of the mimetic peptide were concentration-dependent. High concentrations (100-300 μM) significantly reduced Cx43 protein levels and GJIC within 2 h, while these effects did not appear until 6 h when using lower concentrations (10-30 μM). Cell death can be reduced when hemichannel opening and GJIC were minimised.
Highlights
Connexin (Cx) modulation has been recognised as a target for therapeutic intervention in a number of diseases (Alldredge, 2008; Bennett, 1994; Ormonde et al, 2012; Wei et al, 2004) and there are a series of clinical trials targeting Cxs
Gap27 reduced Cx43 and CxHC levels in normal 3T3 fibroblasts To determine the effect of Cx mimetic peptide on Cx43 gap junction (GJ) and CxHC protein levels, 3T3 cells were treated with different doses of Gap27 for 2 h or 6 h
In the cells treated with Gap27 for 6 h, Cx43 levels were significantly less for all the doses and reached about 60% reduction of Cx43 protein levels compared to no-treatment or scrambled peptide (Fig. 1D)
Summary
Connexin (Cx) modulation has been recognised as a target for therapeutic intervention in a number of diseases (Alldredge, 2008; Bennett, 1994; Ormonde et al, 2012; Wei et al, 2004) and there are a series of clinical trials targeting Cxs. Mimetic peptides that mimic the extracellular loops of Cxs have been reported to influence gap junction and hemichannel function (Warner et al, 1995).
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