ATP is both an important mediator of physiological gut functions such as motility and epithelial function, and a key danger signal that mediates cell death and tissue damage. The actions of extracellular
ATP are regulated through the catalytic functions extracellular
nucleoside triphosphate diphosphohydrolase-1 (
NTPDase1), -2, -3, and -8, which ultimately generate
nucleosides. Ectonucleotidases have distinct cellular associations, but the specific locations and functional roles of individual NTPDases in the intestine are still poorly understood. Here, we tested the hypothesis that differential and cell-selective regulation of
purine hydrolysis by
NTPDase1 and -2 plays important roles in gut physiology and disease. We studied Entpd1 and Entpd2 null mice in health and following
colitis driven by 2%
dextran sulfate sodium (DSS) administration using functional readouts of gut motility, epithelial barrier function, and neuromuscular communication.
NTPDase1 is expressed by immune cells, and the ablation of Entpd1 altered glial numbers in the myenteric plexus.
NTPDase2 is expressed by enteric glia, and the ablation of Entpd2 altered myenteric neuron numbers. Mice lacking either
NTPDase1 or -2 exhibited decreased inhibitory neuromuscular transmission and altered components of inhibitory junction potentials. Ablation of Entpd2 increased gut permeability following
inflammation. In conclusion, the location- and context-dependent extracellular
nucleotide phosphohydrolysis by
NTPDase1 and -2 substantially impacts gut function in health and disease.NEW & NOTEWORTHY
Purines are important mediators of gastrointestinal physiology and pathophysiology.
Nucleoside triphosphate diphosphohydrolases (NTPDases) regulate extracellular
purines, but the roles of specific NTPDases in gut functions are poorly understood. Here, we used Entpd1- and Entpd2-deficient mice to show that the differential and cell-selective regulation of
purine hydrolysis by
NTPDase1 and -2 plays important roles in barrier function, gut motility, and neuromuscular communication in health and disease.