Genomic Priming of the Antisecretory Response to Estrogen in Rat Distal Colon throughout the Estrous Cycle

Abstract

The secretion of Cl− across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17β-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase Cδ (PKCδ) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKCδ 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 estrous, metestrous, and diestrous stages. A weak inhibition of secretion was demonstrated in the proestrous stage. The expression levels of PKCδ and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKCδ and PKA were up-regulated by estrogen at a transcriptional level via a PKCδ-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PKCδ 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-α 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.

17β-Estradiol Inhibits IL-8 in Cystic Fibrosis by Up-Regulating Secretory Leucoprotease Inhibitor

“…ERa has been shown to mediate effectively an antisecretory effect in extrapulmonary tissues, such as the colon (51,52), and more recently within the CF airway through a reduction of the ASL (36). This is induced through the rapid nongenomic effects of E 2 exposure occurring within seconds to minutes affecting calcium mobilization (36).…”

“…Representative single focal plane scans are shown. n 5 4. b versa (52)(53)(54). Cell signaling responses initiated in the rapid phase of estrogen action additionally have been found to persist over hours to days and therefore are not purely nongenomic and in vivo are unlikely to be epiphenomena to the traditional genomic response (55).…”

Novel female sex-dependent actions of oestrogen in the intestine

“…Through the modulation of protein kinase expression, varying circulating levels of oestrogen determine the sensitivity of particular cell signalling cascades to the rapid actions of the hormone. Oestrogen‐induced PKCδ expression effectively creates a positive feedback loop that amplifies PKCδ‐dependent oestrogen rapid and genomic responses at the peak of circulatory levels of oestrogen (O’Mahony et al 2009). More recently this genomic regulation of PKCδ in the female rat distal colon has been demonstrated to be via a novel membrane ERα (memERα) (O’Mahony et al 2009).…”

“…Oestrogen‐induced PKCδ expression effectively creates a positive feedback loop that amplifies PKCδ‐dependent oestrogen rapid and genomic responses at the peak of circulatory levels of oestrogen (O’Mahony et al 2009). More recently this genomic regulation of PKCδ in the female rat distal colon has been demonstrated to be via a novel membrane ERα (memERα) (O’Mahony et al 2009). The memERα is expressed in rat colonic crypts from the male and female but with a reduced expression in the male tissue compared to female (O’Mahony et al 2009).…”

“…More recently this genomic regulation of PKCδ in the female rat distal colon has been demonstrated to be via a novel membrane ERα (memERα) (O’Mahony et al 2009). The memERα is expressed in rat colonic crypts from the male and female but with a reduced expression in the male tissue compared to female (O’Mahony et al 2009).…”