Abstract
Estrogen exerts a female‐specific anti‐secretory response in epithelia via KCNQ1:KCNE3 channel inhibition (O'Mahony et al., 2009. J Physiol. 587:5039–44). The purpose of this study was to determine the molecular mechanisms by which sex and estrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. KCNE1 and KCNE3 mRNA and protein abundance were significantly higher in male than female colonic crypts. KCNQ1 and KCNE3 protein expression fluctuated throughout the estrous cycle and 17β‐estradiol (E2 10 nM) produced a rapid (<15 min) dissociation of KCNQ1 and KCNE3 in female crypts only. The effect of E2 on K+ currents mediated by KCNQ1 with or without different β‐subunits was assayed from current‐voltage relations elicited in CHO cells transfected with KCNQ1 and KCNE3 or KCNE1 cDNA. E2 reduced the currents mediated by the KCNQ1:KCNE3 potassium channel and had no effect on currents via KCNQ1:KCNE1 or KCNQ1 alone. Mutation of a serine to an alanine, S82A, on the cytosolic side of KCNE3, prevented E2 induced PKCδ phosphorylation of KCNE3 and caused insensitivity of KCNQ1 currents to E2. KCNE3 phosphorylation and decreased association of the KCNQ1:KCNE3 channel complex promoted by estrogen underlie the molecular mechanisms for the sexual dimorphism and estrous cycle dependence of the anti‐secretory actions of estrogen in the intestine.
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