Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.
AffiliationDepartment of Molecular Medicine, Royal College of Surgeons in Ireland, Education, and Research Centre, Beaumont Hospital, P.O. Box 9063, Dublin 9, Ireland.
MeSH8-Bromo Cyclic Adenosine Monophosphate/pharmacology
Cyclic GMP/analogs & derivatives/pharmacology
KCNQ1 Potassium Channel/metabolism
Membrane Potentials/drug effects
Protein Kinase C-delta/metabolism
MetadataShow full item record
CitationSteroids. 2011 Aug;76(9):867-76. Epub 2011 May 8.
AbstractExcessive Cl(-) secretion is the driving force for secretory diarrhea. 17beta-Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17beta-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17beta-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. 17beta-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. 17beta-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17beta-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCdelta activation. In nystatin-permeabilized tissues, apical Cl(-) currents were unaffected by 17beta-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, 17beta-estradiol inhibits enterotoxin-induced Cl(-) secretion via a PKCdelta-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17beta-estradiol inhibition of Cl(-) secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases.
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