Khaberni - Scientists at Northwestern University have discovered a new molecular finding that explains how fluid regulation in the intestines works, potentially paving the way for developing more effective treatments for both constipation and diarrhea.
Although constipation and diarrhea appear as contrasting conditions, they have one fundamental cause in common: the amount of fluid that reaches the intestines. Until now, scientists did not fully understand the mechanisms that maintain fluid balance in the digestive system.
In the new study, the research team focused on "Bisacodyl," one of the world's most used laxatives, and discovered that its effect depends on an ion channel called TRPM4, which acts as a key switch controlling the flow of fluids within the intestines.
Juan Doe, the co-author of the study, said: "Despite 'Bisacodyl' being used clinically for over 60 years, the precise molecular target of the drug was unknown. We have succeeded in clarifying its mechanism of action at the atomic level and have reached a comprehensive understanding of its impact on the intestines."
Wei Lu, from Northwestern University, added: "Our results confirm the role of TRPM4 as a central regulator of intestinal fluid balance, identify a new drug target, and provide a roadmap for developing next-generation treatments for digestive system disorders."
How the TRPM4 Channel Works
The significance of the TRPM4 channel lies in the epithelial cells that line the intestinal wall and control the movement of salts and water. When activated by "Bisacodyl," the sodium ions flow into the cells, leading to the activation of the chloride channel, which is an ion channel allowing the exit of chloride ions from the cells to the intestinal cavity. This ion flow naturally pulls water with it, producing a laxative effect and helping to move fluids in the intestines.
While scientists knew that TRPM4 responds to internal calcium signals, the study team discovered that "Bisacodyl" activates the channel in a manner independent of calcium. Using cryo-electron microscopy, the team identified a new molecular pocket that binds the drug and activates the channel.
To confirm the channel's role, the scientists tested "Bisacodyl" on genetically modified mice lacking TRPM4. In normal mice, the drug increased water content in the feces and made it softer, while no effect was observed in the modified mice.
The Importance of the Discovery
This discovery represents a significant advancement in understanding how intestinal fluids are regulated and provides opportunities for developing precise drugs to treat chronic constipation or diarrhea. This scientific work builds on years of intensive studies on the TRPM4 channel, detailing how the channel is constructed, opened, closed, its response to temperature, and its linkage with drugs.
The study results were published in the journal Nature Communications.
