Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis

  • Nat Commun. 2026 Jan 8;17(1):1253. doi: 10.1038/s41467-025-68014-7.
Yaru Liu  #  1  2 ,  Jinhong Hu  #  3 ,  Chu Xue  #  1 ,  Wenjie Huang  #  1 ,  Sofia Ievleva  3  4 ,  Wei Lü  5  6  7 ,  Juan Du  8  9  10 ,  Zhengyu Cao  11  12
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 2. Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 3. Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • 4. Van Andel Institute, Grand Rapids, MI, USA.
  • 5. Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA. [email protected].
  • 6. Department of Pharmacology, Northwestern University; Feinberg School of Medicine, Chicago, IL, USA. [email protected].
  • 7. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA. [email protected].
  • 8. Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA. [email protected].
  • 9. Department of Pharmacology, Northwestern University; Feinberg School of Medicine, Chicago, IL, USA. [email protected].
  • 10. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA. [email protected].
  • 11. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China. [email protected].
  • 12. Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 41507162 DOI: 10.1038/s41467-025-68014-7
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.

Products