Purinergic Signaling in Gut Inflammation: The Role of Connexins and Pannexins

Abstract

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.

Keywords: connexins; gastrointestinal inflammation; inflammatory bowel disease; pannexins; purinergic receptors.

Figure 1

Cell type-specific schema of ATP release and action. ATP (red triangles) can be released from the cell cytosol to the extracellular space (dashed red line) via Panx1 channels or Cx43 hemichannels (pictured). Once in the extracellular space, this ATP acts as a paracrine transmitter, as can ATP released from nearby cells that are dead or dying (not shown). Extracellular ATP can activate P2 receptors, such as P2X7R (pictured) that depolarises the target cell, but also activates an inflammatory response in immune cells (dashed gray line) with subsequent release of cytokines such as IL-1β that can act back at Panx1 and Cx43 to modulate their function (dashed gray lines). Activation of P2X7R also mediates the T-cell response (e.g., Ca²⁺ entry, IL-2 synthesis) and macrophage migration (not shown).