Abstract
The Ca2+-activated Cl− channel TMEM16A is involved in epithelial fluid secretion, smooth muscle contraction and neurosensory signaling. We identified a Thai herbal antidiarrheal formulation that inhibited TMEM16A Cl− conductance. C18-reversed-phase HPLC fractionation of the herbal formulation revealed >98% of TMEM16A inhibition activity in one out of approximately 20 distinct peaks. The purified, active compound was identified as eugenol (4-allyl-2-methoxyphenol), the major component of clove oil. Eugenol fully inhibited TMEM16A Cl− conductance with single-site IC50∼150 µM. Eugenol inhibition of TMEM16A in interstitial cells of Cajal produced strong inhibition of intestinal contraction in mouse ileal segments. TMEM16A Cl− channel inhibition adds to the list of eugenol molecular targets and may account for some of its biological activities.
Highlights
Intestinal fluid secretion in secretory diarrheas involves Cl2 movement from the blood to the intestinal lumen through Cl2 channels on the enterocyte apical plasma membrane
TMEM16A has been identified as a Ca2+-activated Cl2 channels (CaCCs) that is broadly expressed in tracheal, intestinal and glandular epithelia, smooth muscle cells, and gastrointestinal interstitial cells of Cajal, where it is involved in epithelial fluid secretion, smooth muscle contraction and gastrointestinal motility [6,7,8]
We discovered that gallotannin-containing red wines and green teas inhibit CaCC/ TMEM16A activity, which may account for their reported beneficial effects in cardiovascular disease and secretory diarrheas [11]
Summary
Intestinal fluid secretion in secretory diarrheas involves Cl2 movement from the blood to the intestinal lumen through Cl2 channels on the enterocyte apical plasma membrane. These Cl2 channels include a cAMP-gated channel, CFTR (cystic fibrosis transmembrane conductance regulator), and Ca2+-activated Cl2 channels (CaCCs), one of which has been identified as TMEM16A [1,2]. By high-throughput screening, several small-molecule inhibitors and activators of TMEM16A Cl2 conductance [9,10], which have potential therapeutic value in cystic fibrosis, dry mouth, gastric hypomotility (activators), secretory diarrhea, pain and tumor growth (inhibitors). We discovered that gallotannin-containing red wines and green teas inhibit CaCC/ TMEM16A activity, which may account for their reported beneficial effects in cardiovascular disease and secretory diarrheas [11]
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