The Role of Connexin Hemichannels in Inflammatory Diseases

Abstract

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.

Keywords: ATP; HMGB1; channel blocker; connexin hemichannel; gap junctions; inflammation; innate immune cells; ischemia; mimetic peptide; sepsis.

Figure 1

Schematic diagram of a gap junction, hemichannel and connexin. The membrane topology of a connexin protein is shown on the right. NT, N-terminal; EL, extracellular loop; CL, cytoplasmic loop; CT, carboxyl terminal. Green arrows indicate the gap junction and hemichannel pores that allow the passage of small molecules.