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However, its direct impact on network\u2010forming interstitial cells of Cajal (ICCs), whose pacemaker activity enables flexible and coordinated gut movement, remains unclear. This study investigated the effect of melatonin on ICC electrical activity and micro\u2010coordination in the murine ileum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Electrical activity was recorded from ileal musculature using a dialysis membrane\u2010reinforced 8\u2009\u00d7\u20098 microelectrode array (MEA), allowing visualisation of spatio\u2010temporal coordination. Smooth muscle contraction and neuronal activity were suppressed using nifedipine and tetrodotoxin (TTX), respectively. RT\u2010qPCR was used to assess melatonin receptor and antioxidant enzyme expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Functionally relevant concentrations of melatonin (10\u201320\u2009\u03bcM) increased the frequency of electrical slow waves without affecting amplitude or propagation patterns. This excitatory effect was blocked by the melatonin receptor antagonists, luzindole and 4P\u2010PDOT, and was associated with MT2 receptor expression. In contrast, supraphysiological concentrations (500\u2009\u03bcM\u20131\u00a0mM) suppressed both frequency and amplitude and increased the incidence of expanding activity patterns. This inhibitory effect was luzindole\u2010insensitive but was mimicked by 3\u2010indolepropionic acid (IPA), a gut microbiota\u2010derived indole with antioxidant properties. High\u2010dose melatonin also upregulated Nrf2 and its downstream antioxidant enzymes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Melatonin modulates ICC networks in a concentration\u2010dependent manner: stimulation via MT2 signalling at functionally relevant levels and inhibition via antioxidant pathways at supraphysiological levels. These findings indicate that ICC networks contribute to melatonin responses and reveal distinct receptor\u2010dependent and redox\u2010dependent mechanisms regulating gastrointestinal pacemaker networks.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70658","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:23:22Z","timestamp":1787808202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Melatonin exerts dual, concentration\u2010dependent effects on intestinal pacemaker networks via MT2 receptor activation and redox pathways"],"prefix":"10.1111","author":[{"given":"Md. 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