Functional Expression of Large-Conductance Calcium-Activated Potassium Channels in Human Endometrium: A Novel Mechanism Involved in Endometrial Receptivity and Embryo Implantation

Background: Large-conductance calcium-activated potassium channels (BKCa channels) mediate physiological processes in nonexcitable cells. Objective: The aim of the study was to determine BKCa channel expression in human endometrium and its role in endometrial receptivity and embryo implantation. Methods: BKCa channel expression in human endometrium is described at different phases of the menstrual cycle using quantitative real time-PCR and Western blot techniques. Their effects on embryo implantation were examined using JAr spheroid attachment assays and in vivo mouse model. We examined their effects on endometrial receptivity factors, nuclear factor-kappa B (NF-kappa B) activity using quantitative real time-PCR, Western blot, and EMSA analyses. Changes in electro-physiological properties and cytosolic free Ca2+ were measured in endometrial cells with or without specific BKCa blocker or transfected with BKCa small interfering RNA using patch-clamp and fluorescence analyses, respectively. Results: BKCa channels are expressed in human endometrial cells in a phase-related fashion during the menstrual cycle (proliferative, 0.20 +/- 0.02, vs. mid-secretory, 0.72 +/- 0.07; P < 0.01). Blocking BKCa channel function or knockdown of endogenous BKCa channel expression not only decreased JAr spheroid attachment rate and embryo implantation rate in mice but also significantly reduced the expression levels of endometrial receptive factors, including leukemia inhibitory factor, integrin beta 3, claudin-4, and DKK-1, in human endometrial cells. Blocking BKCa channels also reduced BKCa-regulated NF-kappa B activity, cytosolic Ca2+ concentrations, and membrane potentials in human endometrial cells. Conclusions: These observations demonstrate that BKCa channels: 1) are expressed in endometrial cells; 2) affect embryo implantation by mediating endometrial receptive factors; and 3) alter the activity of NF-kappa B and homeostasis of Ca2+ in the human endometrial cells. (J Clin Endocrinol Metab 97: 543-553, 2012)