Activation of neuronal P2X7 receptor–pannexin-1 mediates death of enteric neurons during colitis
Open Access
- 18 March 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 18 (4), 600-604
- https://doi.org/10.1038/nm.2679
Abstract
Enteric neuron death is linked to the pathogenesis of inflammatory bowel disease. Now, Brian Gulbransen and his colleagues demonstrate that P2X7 receptor–pannexin-1 signaling is responsible for enteric neuron death in mouse models of colitis. Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons1,2. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.This publication has 38 references indexed in Scilit:
- Rho Signaling Regulates Pannexin 1-mediated ATP Release from Airway EpitheliaOnline Journal of Public Health Informatics, 2011
- Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosisNature, 2010
- Stimulation of the P2X7 receptor kills rat retinal ganglion cells in vivoExperimental Eye Research, 2010
- Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colonJournal Of Physiology-London, 2010
- CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel diseaseProceedings of the National Academy of Sciences of the United States of America, 2009
- The Pannexin 1 Channel Activates the Inflammasome in Neurons and AstrocytesJournal of Biological Chemistry, 2009
- New bioinformatics approach to analyze gene expressions and signaling pathways reveals unique purine gene dysregulation profiles that distinguish between CD and UCInflammatory Bowel Diseases, 2009
- Plasticity of enteric nerve functions in the inflamed and postinflamed gutNeurogastroenterology & Motility, 2009
- Chemically induced mouse models of intestinal inflammationNature Protocols, 2007
- Pannexin1 is part of the pore forming unit of the P2X7 receptor death complexFEBS Letters, 2007