Mechanisms Underlying Connexin Hemichannel Activation in Disease

Abstract

Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the "good guys" by controlling homeostasis, connexin hemichannels are considered as the "bad guys", as their activation is associated with the onset and dissemination of disease. Open connexin hemichannels indeed mediate the transport of messengers between the cytosol and extracellular environment and, by doing so, fuel inflammation and cell death in a plethora of diseases. The present mini-review discusses the mechanisms involved in the activation of connexin hemichannels during pathology.

Keywords: connexin hemichannel; mechanism; pathology.

Figure 1

Architecture of gap junction, connexin hemichannels and connexin proteins. Gap junctions arise from the interaction of two connexin hemichannels of adjacent cells. A connexin hemichannel is built up by six connexin proteins. A connexin protein consists of four transmembrane domains (TM1-4), two extracellular loops (EL1-2), one cytosolic loop (CL), one cytosolic carboxyterminal tail (CT) and one cytosolic amino tail (NT).

Figure 2

Role of connexin hemichannels in canonical inflammation activation. Canonical inflammasome activation requires two signals. (1) Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) interact with Toll-like receptors of immune cells to induce inflammation. The binding of DAMPs and PAMPs promotes the transfer of nuclear factor (NF)-κβ to the nucleus to activate gene expression. Thus, the transcription of the genes encoding premature forms of interleukin (IL)-1β and IL-18 is triggered. (2) Pathogenic stimuli drive the opening of connexin hemichannels, promoting the extracellular release of adenosine triphosphate (ATP). Extracellular ATP molecules stimulate P2X7 receptors, leading to nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLP3) inflammasome activation. NLP3 inflammasome activation triggers the onset of caspase 1, which influences the inflammatory process by cleaving pro-IL-1β and pro-IL-18 to their mature form and producing other pro-inflammatory cytokines.