Giant migrating contractions (GMCs) are powerful waves of colonic movement that propel intestinal contents toward the anus and are essential for defecation. Yet despite their physiological importance, the mechanisms that initiate these contractions—and particularly the factors that regulate spontaneous GMCs—have remained poorly understood. While several mediators, including 5-hydroxytryptamine (5-HT), calcitonin gene-related peptide (CGRP), and substance P, have been implicated in colonic motility, the core regulatory machinery has not been clearly defined. Adenosine triphosphate (ATP), meanwhile, is well known for its roles in pain signaling and intestinal dysfunction during inflammation, but its contribution to normal colonic motor function has remained unclear.
Now, a research team from Saitama University has identified ATP-P2X7 signaling as a previously unrecognized neural mechanism that drives colonic GMCs. The team was led by master's students Ayano Gomi and Hozuki Shimosawa together with Professor Ichiro Sakata, and used Suncus murinus (suncus), an animal model that allows colonic motility to be examined under conscious conditions.
The study was first published online on March 26, 2026, and appeared in The FASEB Journal on March 31, 2026.
To investigate whether ATP functions as a regulator of GMCs, the researchers measured colonic motility in conscious, freely moving suncus. Intravenous administration of ATP rapidly induced strong GMC-like contractions at doses of 5–200 mg/kg. Notably, the amplitude and duration of these contractions closely resembled those of spontaneous GMCs, suggesting that ATP may act as a major regulator of this defecation-related motor pattern.
The researchers then asked whether ATP acts directly on the colon itself. In organ bath experiments using isolated colonic tissue, acetylcholine induced clear contractions, whereas cumulative ATP administration failed to trigger any contractile response. This finding indicates that ATP does not directly stimulate colonic smooth muscle, but instead acts through a neural mechanism.
Further pharmacological analysis clarified the pathway involved. Neither ADP nor adenosine—metabolites of ATP—induced comparable contractions, and non-selective P2 receptor antagonists did not suppress ATP-induced GMCs. In contrast, ATP-induced contractions were abolished by the selective P2X7 receptor antagonists Brilliant Blue G (BBG) and A-740003. Conversely, bzATP, a potent P2X7 receptor agonist, reproduced strong GMC-like contractions. In addition, atropine, which blocks cholinergic signaling, completely suppressed ATP-induced GMCs. Together, these results indicate that ATP activates cholinergic neurons via the P2X7 receptor, thereby triggering GMCs.
The findings are particularly significant because they identify a new ATP-P2X7-cholinergic neural pathway that drives the powerful colonic contractions required for defecation. By revealing this mechanism, the study adds a new dimension to the biology of gastrointestinal motility and provides fresh insight into how colonic propulsion is controlled in vivo.
"This work introduces purinergic signaling as a new perspective in understanding the regulation of GMCs, a process that has not been fully explained until now," says Professor Ichiro Sakata. "Most importantly, it shows that ATP is not merely a molecule involved in inflammation or pain, but can actively drive the powerful colonic motor patterns required for defecation. The fact that this phenomenon was clearly observed in conscious animals, but not reproduced in isolated tissue, also underscores the importance of extrinsic neural circuits and central regulatory pathways in GMC control. We hope that further investigation into the localization of the P2X7 receptor and its relationship to spontaneous GMCs will help move this field forward."
The researchers also believe the study may have longer-term clinical and translational implications. "Our findings suggest that ATP-P2X7 signaling could become a promising therapeutic target for colonic motility disorders associated with constipation and difficulty in defecation," says Ayano Gomi. "Over the next five to ten years, advances in the development of P2X7-related compounds and other motility-regulating agents may contribute to improving patients' quality of life. These findings may also have broader applications in areas such as drug discovery, functional foods, and gastrointestinal assessment technologies, where they could provide a new indicator for evaluating neurally regulated colonic motility. In an aging society, where defecation-related problems are becoming increasingly common, the potential impact could be considerable."
