Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases

Abstract

P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.

Macrophage regulation of the “second brain”: CD163 intestinal macrophages interact with inhibitory interneurons to regulate colonic motility - evidence from the Cx3cr1-Dtr rat model

“…Purinergic neurotransmission may also play a role in the inhibitory regulation of gut motility ( 62 , 63 ). P2X receptors are expressed in the submucosal plexus, myenteric plexus, as well as the smooth muscle layers ( 64 ). In particular, P2X2R receptors localized in intermuscular neurons are involved in the regulation of smooth muscle contraction ( 65 ).…”

Altered gut microbial functional pathways in people with Irritable Bowel Syndrome enable precision health insights

“…However, several studies support a link between purine levels and IBS subtypes [68][69][70][71], and there are welldocumented associations between high uric acid levels (hyperuricemia) and inflammatory diseases (i.e., gout [72,73], hypertension [74], metabolic syndrome [75], and chronic kidney disease [76]) which are, in turn, associated with IBS or its subtypes [65,[77][78][79]. Furthermore, purinergic receptors are implicated in secretomotor reflexes of the gastrointestinal tract [80][81][82] and are actively pursued as IBS drug targets [83,84].…”

Ion channels in dry eye disease

“…Purinergic receptors (P2X; P2Y) are ligand-gated, nonselective cationic ion channels that are activated by extracellular ATP and are permeable to sodium, potassium, and calcium ions. [ 111 - 113 ] Tissue injury and inflammation results in the release of extracellular ATP which could activate P2X and P2Y purinergic receptors and initiate nociception in peripheral afferents. [ 111 ] ATP binding of P2X receptors leads to release of inflammatory cytokines; P2X1 and P2X7 play role in this immunomodulation.…”

“…[ 111 - 113 ] Tissue injury and inflammation results in the release of extracellular ATP which could activate P2X and P2Y purinergic receptors and initiate nociception in peripheral afferents. [ 111 ] ATP binding of P2X receptors leads to release of inflammatory cytokines; P2X1 and P2X7 play role in this immunomodulation. [ 114 ] Immune cells at the site of inflammation contains increased expression of P2X receptors.…”