Coumarins attenuate intestinal motility by inhibiting TMEM16A

Area of Science:

• Gastroenterology
• Ion Channel Physiology
• Pharmacology

Background:

• Transmembrane 16A (TMEM16A) is crucial for intestinal motility and fluid secretion, with its dysfunction linked to gastrointestinal disorders.
• Unidentified calcium-activated chloride channels (unCaCCs) are primarily responsible for intestinal fluid secretion, but TMEM16A also plays a role.
• Identifying regulators of TMEM16A/CaCCs is vital for understanding and treating related physiopathological conditions.

Purpose of the Study:

• To identify TMEM16A inhibitors and investigate their effects on intestinal motility and ion channel function.
• To explore the potential of coumarins as therapeutic agents for conditions involving TMEM16A/CaCCs dysfunction.
• To elucidate the specific ion channel targets and mechanisms of action for coumarins in the intestinal epithelium.

Main Methods:

• Screening for TMEM16A inhibitors using TMEM16A-expressed Fischer rat thyroid (FRT) epithelial cells.
• Assessing the effects of coumarins on intestinal motility ex vivo and in vivo.
• Measuring Ca2+-activated Cl- currents (CaCCs) in T84, HT-29 cells, and mouse colonic mucosa using electrophysiology.
• Investigating effects on intracellular calcium concentrations, Ca2+-activated K+ channels, Na+/K+-ATPase, and CFTR-mediated currents.

Main Results:

• Coumarins were identified as concentration- and time-dependent inhibitors of TMEM16A.
• Coumarins attenuated intestinal motility in vivo and ex vivo by inhibiting TMEM16A.
• Coumarins inhibited CaCCs-mediated currents and reduced intracellular Ca2+ in intestinal cells, without affecting CFTR significantly.
• Coumarins inhibited basolateral Ca2+-activated K+ channels but not Na+/K+-ATPase activity.

Conclusions:

• Coumarins effectively inhibit TMEM16A, providing a novel approach to modulating intestinal motility.
• The findings suggest coumarins can reduce intestinal motility by targeting TMEM16A, offering a potential strategy for managing secretory diarrhea.
• This study highlights coumarins as valuable tools for studying TMEM16A/CaCCs and their role in gastrointestinal physiology and pathology.