Abstract
Simple SummaryConnexin hemichannels are formed by connexin protein family members, and connect cytosol and extracellular milium. The function of connexin hemichannels cannot be readily distinguished from the gap junctions formed also by connexins, or hemichannels formed by pannexins. It appears that connexin hemichannels are normally closed to maintain cellular homeostasis, but can be activated in pathophysiological processes to serve as toxic membrane pores. On the other hand, gap junctions are normally open in order to perform critical physiological functions, but are often closed or down-regulated under pathological conditions. The development and characterization of connexin mimetic peptides have resulted in a panel of connexin hemichannel-selective blockers. Investigations using these blockers have shown that the opening of connexin hemichannels facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of connexin hemichannels virtually always leads to attenuated inflammation, reduced tissue injury and improved organ function. In this review, we provide an updated view of the role of connexin hemichannels in inflammatory diseases.The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on the membranes of apposing cells. Non-junctional connexin hemichannels (CxHC) provide a conduit between the cell interior and the extracellular milieu, and are believed to be in a protectively closed state under physiological conditions. The development and characterization of the peptide mimetics of the amino acid sequences of connexins have resulted in the development of a panel of blockers with a higher selectivity for CxHC, which have become important tools for defining the role of CxHC in various biological processes. It is increasingly clear that CxHC can be induced to open by pathogen-associated molecular patterns. The opening of CxHC facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of CxHC leads to attenuated inflammation, reduced tissue injury and improved organ function in human and animal models of about thirty inflammatory diseases and disorders. These findings demonstrate that CxHC may contribute to the intensification of inflammation, and serve as a common target in the treatments of various inflammatory diseases. In this review, we provide an update on the progress in the understanding of CxHC, with a focus on the role of these channels in inflammatory diseases.
Highlights
Connexins are a family of transmembrane proteins encoded by 21 connexin genes in humans and 20 in mice [1,2]
The involvement of connexin hemichannels (CxHC) in sepsis pathogenesis was first implicated when we examined the effect of carbenoxolone, a common gap junction and hemichannel blocker, on sepsis lethality in a mouse model of polymicrobial sepsis
There is evidence supporting the possibility that high-mobility group box-1 (HMGB1) may be secreted in exosomes or microvesicles in a manner regulated by Cx43HC. We found that both the hemichannel permeability of LPS-challenged macrophages and the HMGB1 level in culture medium can be reduced by carbenoxolone, a non-selective connexin and pannexin channel blocker [113]
Summary
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