2026-01-12 ノースウェスタン大学
By studying one of the world’s most widely used laxatives, Northwestern researchers have uncovered a key molecular switch that helps control the gut’s “water faucet.”
<関連情報>
- https://news.northwestern.edu/stories/2026/01/control-valve-discovered-in-guts-plumbing-system
- https://www.nature.com/articles/s41467-025-68014-7
非典型的なカルシウム非依存性TRPM4活性化が腸液恒常性を制御する Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis
Yaru Liu,Jinhong Hu,Chu Xue,Wenjie Huang,Sofia Ievleva,Wei Lü,Juan Du & Zhengyu Cao
Nature Communications Published:08 January 2026
DOI:https://doi.org/10.1038/s41467-025-68014-7 An unedited version of this manuscript
Abstract
Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium-activated, non-selective monovalent cation channel converting chemical signals (Ca2+) into electrical signals (membrane depolarization). Here, we show the TRPM4 channel as a direct target of bisacodyl (BIC), a widely used clinical drug for chronic constipation management, and its active metabolite, deacetyl bisacodyl (DAB). DAB-induced laxative effects are abolished in global and intestinal epithelium-specific TRPM4-knockout mice, establishing the essential role of TRPM4 in intestinal fluid regulation. Furthermore, our structural work reveals DAB bound to an uncharacterized pocket, marking it as a non-Ca2+ TRPM4 agonist and unveiling a noncanonical Ca2+-independent activation mechanism. Additionally, we delineate a signaling axis, TRPM4 → VGCC/NCX → ANO1, that governs ion homeostasis in the epithelium. Together, these findings establish TRPM4 as a key regulator of intestinal fluid balance and reveal its noncanonical calcium-independent activation as a therapeutic strategy for constipation.
