The presence of Panx1 in the colon and changes to its distribution in disease suggests that Panx1 channels may play an important role in mediating gut function and in IBD pathophysiology.

Purinergic receptors play an important role in inflammation, and can be activated by ATP released via pannexin channels and/or connexin hemichannels. The purinergic P2X7 receptor (P2X7R) is of interest since it is involved in apoptosis when activated. Most studies focus on the influence of pannexin-1 (Panx1) and connexin 43 (Cx43) on ATP release and how it affects P2X7R function during inflammation. Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation within the gastrointestinal system. At present, the pathophysiology of this disease remains largely unknown but it may involve the interplay between P2X7R, Panx1, and Cx43. There are two main types of IBD, ulcerative colitis and Crohn's disease, that are classified by their location and frequency of inflammation. Current research suggests that alterations to normal functioning of innate and adaptive immunity may be a factor in disease progression. The involvement of purinergic receptors, connexins, and pannexins in IBD is a relatively novel notion in the context of gastrointestinal inflammation, and has been explored by various research groups. Thus, the present review focuses on the current research involving connexins, pannexins, and purinergic receptors within the gut and enteric nervous system, and will examine their involvement in inflammation and the pathophysiology of IBD.

Introduction: The pannexin-1 (Panx1) channels are found in many cell types, and ATP released from these channels can act on nearby cells activating purinergic P2X7 receptors (P2X7R) which lead to inflammation. Although Panx1 and P2X7R are implicated in the process of inflammation and cell death, few studies have looked at the role they play in inflammatory bowel disease in human. Hence, the aim of the present study was to investigate the function of Panx1 and P2X7R in an ex vivo colitis model developed from human colonic mucosal explants.Materials and Methods: Healthy human colonic mucosal strips (4 × 10 mm) were incubated in carbogenated culture medium at 37°C for 16 h. Proinflammatory cytokines TNFα and IL-1β (each 10 ng/mL) were used to induce colitis in mucosal strips, and the effects of Panx1 and P2X7R on cytokines-induced tissue damage were determined in the presence of the Panx1 channel blocker 10Panx1 (100 μM) and P2X7R antagonist A438079 (100 μM). The effects of 10Panx1 and A438079 on cytokines-enhanced epithelial permeability were also studied using Caco-2 cells.Results: Histological staining showed that the mucosal strips had severe structural damage in the cytokines-only group but not in the incubation-control group (P < 0.01). Compared to the cytokines-only group, crypt damage was significantly decreased in groups receiving cytokines with inhibitors (10Panx1, A438079, or 10Panx1 + A438079, P < 0.05). The immunoreactive signals of tight junction protein zonula occludens-1 (ZO-1) were abundant in all control tissues but were significantly disrupted and lost in the cytokines-only group (P < 0.01). The diminished ZO-1 immunoreactivity induced by cytokines was prevented in the presence of 10Panx1 (P = 0.04). Likewise, 10Panx1 significantly attenuated the cytokines-evoked increase in paracellular permeability of Caco-2 cells. Although the inhibition of P2X7R activity by A438079 diminished cytokines-induced crypt damage, its effect on the maintenance of ZO-1 immunoreactivity and Caco-2 epithelial cell integrity was less evident.Conclusion: The blockade of Panx1 and P2X7R reduced the inflammatory cytokines-induced crypt damage, loss of tight junctions and increase in cell permeability. Thus, Panx1 and P2X7R may have roles in causing mucosal damage, a common clinical feature of inflammatory bowel disease.

Here, we demonstrated the dense expression of Panx2 in the enteric nervous system and the co-localization of Panx2 with a spectrum of neuronal markers, indicating that Panx2 may be involved in mediating neurotransmission in the colon. The substantial increase in Panx2 mRNA in UC muscle but not protein suggests that the Panx2 translation process may be disrupted in UC.