8-Bromo Cyclic Adenosine Monophosphate, Androgens, Animals, Bacterial Toxins, Chloride Channels, Chlorides, Cholera Toxin, Colon, Cyclic GMP, Enterotoxins, Enzyme Activation, Epithelium, Escherichia coli, Estradiol, Estrogens, Female, KCNQ1 Potassium Channel, Male, Membrane Potentials, Progesterone, Progestins, Protein Kinase C-delta, Rats, Rats, Sprague-Dawley, Testosterone
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 1nM. 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.
Medical Molecular Biology | Medical Sciences
Alzamora R, O'Mahony F, Harvey BJ. Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon. Steroids. 2011;76(9):867-76.