Genomic priming of the antisecretory response to estrogen in rat distal colon throughout the estrous cycle.
The secretion of Cl(-) across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17beta-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase C delta (PKC delta) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKC delta in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1-10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrus, metestrus, and diestrus stages. A weak inhibition of secretion was demonstrated in the proestrus stage. The expression levels of PKC delta and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKC delta and PKA were up-regulated by estrogen at a transcriptional level via a PKC delta-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PK Cdelta was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-alpha isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses.
O'Mahony
Fiona
F
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre Smurfit Building, Beaumont Hospital, P.O. Box 9063, Dublin 9, Ireland. fomahony@rcsi.ie
Alzamora
Rodrigo
R
Chung
Ho-Lam
HL
Thomas
Warren
W
Harvey
Brian J
BJ
D000818:Animals; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D023281:Genomics; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D020033:Protein Isoforms; D051745:Protein Kinase C-delta / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic
D004967:Estrogens; D020033:Protein Isoforms; D012333:RNA, Messenger; D004958:Estradiol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D051745:Protein Kinase C-delta