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TitleNoncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJan 8, 2026
AuthorsYaru Liu / Jinhong Hu / Chu Xue / Wenjie Huang / Sofia Ievleva / Wei Lü / Juan Du / Zhengyu Cao /
PubMed AbstractImbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium- ...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 (Ca) 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-Ca TRPM4 agonist and unveiling a noncanonical Ca-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.
External linksNat Commun / PubMed:41507162
MethodsEM (single particle)
Resolution3.2 - 3.4 Å
Structure data

72405

9y2a

EMDB-72405, PDB-9y2a:
Cryo-EM structure of the human TRPM4 channel in complex with calcium and DAB at 37 degrees Celsius
Method: EM (single particle) / Resolution: 3.3 Å

72406

9y2b

EMDB-72406, PDB-9y2b:
Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
Method: EM (single particle) / Resolution: 3.2 Å

72407

9y2c

EMDB-72407, PDB-9y2c:
Cryo-EM structure of the human TRPM4 channel subunit in complex with calcium and DAB at 37 degrees Celsius
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-CA:
Unknown entry

PDB-1cr0:
CRYSTAL STRUCTURE OF THE HELICASE DOMAIN OF THE GENE4 PROTEIN OF BACTERIOPHAGE T7

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / ion channel / TRP channel

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