Role of the A2B receptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats.

Background and Purpose Adenosine A_2B receptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A_2B receptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS). Colonic A_2B receptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A_2B receptors and adenosine deaminase was assayed by immunoprecipitation. The role of A_2B receptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results A_2B receptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A_2B receptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A_2B receptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A_2B receptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A_2B receptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications Under normal conditions, endogenous adenosine modulates colonic motility via A_2B receptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A_2B receptors and adenosine deaminase, which catabolizes adenosine, thus preventing A_2B receptor activation. [ABSTRACT FROM AUTHOR]