Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon

► Estrogen inhibits colonic secretion induced by cholera toxin and heat stable entrotoxin. ► Estrogen inhibits KCNQ1 channels. ► Estrogen inhibition of colonic secretion is female-specific. ► Estrogen protects against secretory diarrhea. ► KCNQ1 channels are a target to treat secretory diarrhea. Excessive Cl − secretion is the driving force for secretory diarrhea. 17β-Estradiol has been shown to inhibit Cl − secretion in rat distal colon through a nongenomic pathway. We examined whether 17β-estradiol inhibits Cl − secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17β-estradiol on cholera toxin and heat-stable enterotoxin induced Cl − secretion in rat colonic mucosal sheets was studied by current–voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral K + channel and apical Cl − channel activity, respectively. 17β-Estradiol dose-dependently inhibited secretory responses to both toxins with IC 50 values of approximately 1 nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17β-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17β-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCδ activation. In nystatin-permeabilized tissues, apical Cl − currents were unaffected by 17β-estradiol treatment while basolateral K + current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17β-estradiol inhibits enterotoxin-induced Cl − secretion via a PKCδ-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17β-estradiol inhibition of Cl − secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases.