10779/rcsi.10787036.v1
Rodrigo Alzamora
Rodrigo
Alzamora
Fiona O'Mahony
Fiona
O'Mahony
Brian J. Harvey
Brian J.
Harvey
Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.
Royal College of Surgeons in Ireland
2019
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
Sprague-Dawley
Testosterone
Molecular Medicine
2019-11-22 16:42:06
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/Estrogen_inhibits_chloride_secretion_caused_by_cholera_and_Escherichia_coli_enterotoxins_in_female_rat_distal_colon_/10787036
<p>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.</p>