Connexin Channel-Dependent Signaling Pathways in Inflammation

Abstract

Inflammation is a highly regulated process with common but also specific characteristics in each tissue affected. Recruitment of leukocytes from the blood to the injured tissue is an important early step in the inflammatory cascade. This review highlights the role of connexins (Cxs) in the regulation of both acute and chronic inflammatory processes. Cxs form gap junction channels that provide a cytoplasmic continuity between adjacent cells allowing the intercellular exchange of ions and metabolites. Their structural halves form connexons or hemichannels. Each of them consists of 6 Cx proteins and hemichannels not taking part in gap junction formation but facilitating the release of small molecules such as ATP. Based on the differential distribution of various Cxs in different tissues such as the brain, lung capillaries and large blood vessels, our aim was to analyze the specific roles of Cxs in the inflammatory process in these tissues. Three typical sites of inflammation were chosen to shed light on similarities and differences in several types of responses: (1) atherosclerosis as a model for chronic inflammation, (2) the lung as an example of acute inflammation and (3) the ‘immune-privileged’ environment of the brain to highlight specific reactions of the vasculature to ischemic damage and inflammation at this site.

Permeation of Calcium through Purified Connexin 26 Hemichannels

“…For this, it is essential to use a purified and reconstituted preparation of HCs where there is no possibility of Ca 2ϩ transport through parallel unidentified pathways. Our results support previous interpretations that suggested a role of Ca 2ϩ fluxes through GJCs and HCs in physiological and pathophysiological conditions (17,21,(25)(26)(27)(28). Ca 2ϩ permeability is relatively high, similar to that for Na ϩ .…”

“…Although most cells have fewer HCs than GJCs at the plasma membrane, the much higher extracellular [Ca 2ϩ ] suggests that HCs can have a significant role in Ca 2ϩ influx, at least under certain circumstances (17,21,(25)(26)(27)(28) or in disease-causing mutants that display higher Ca 2ϩ permeability (G45E mutant associated with keratitis ichthyosis deafness syndrome) (29). In summary, our results showed that Cx26 HCs are permeable to Ca 2ϩ and suggest that HCs can be a pathway for Ca 2ϩ influx into cells under conditions such as ischemia.…”

“…However, HCs can be activated in the presence of millimolar extracellular [Ca 2ϩ ] under a number of conditions, including ischemia, inflammation, connexin dephosphorylation, and extracellular alkalinization (25)(26)(27)(28). Understanding Ca 2ϩ permeation through Cx26 HCs is also important because increased Ca 2ϩ permeability may constitute the bases * This work was supported, in whole or in part, by National Institutes of Health for the association of the G45E mutant with the keratitis ichthyosis deafness syndrome (29).…”

Molecular Biology of Atherosclerosis

“…The relevance of purinergic signaling to atherosclerosis has been illustrated by a series of genetic mouse models (1551). Monocyte Cx37 serves as a hemichannel for release of ATP (see FIGURE 14).…”

Connections in chronic kidney disease: connexin 43 and connexin 37 interaction

“…However, gap junctions have been shown to be disrupted by inflammation (21) and oxidative stress (27). Paired connexins (connexons) play an important role in gap-junctional intercellular communication while unpaired connexins allow communication between the cytosol and extracellular environment.…”