A role for two‐pore potassium (K2P) channels in endometrial epithelial function

Suraj K Patel,Averil Y Warren,Leigh Jackson,Robert W Shaw,Pratibha Arya,Raheela N Khan

doi:10.1111/j.1582-4934.2012.01656.x

Suraj K Patel, Averil Y Warren + Show 4 more

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https://doi.org/10.1111/j.1582-4934.2012.01656.x

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Abstract

The human endometrial epithelium is pivotal to menstrual cycle progression, implantation and early pregnancy. Endometrial function is directly regulated by local factors that include pH, oxygen tension and ion concentrations to generate an environment conducive to fertilization. A superfamily of potassium channels characterized by two-pore domains (K2P) and encoded by KCNK genes is implicated in the control of the cell resting membrane potential through the generation of leak currents and modulation by various physicochemical stimuli. The aims of the study were to determine the expression and function of K2P channel subtypes in proliferative and secretory phase endometrium obtained from normo-ovulatory women and in an endometrial cancer cell line. Using immunochemical methods, real-time qRT-PCR proliferation assays and electrophysiology. Our results demonstrate mRNA for several K2P channel subtypes in human endometrium with molecular expression of TREK-1 shown to be higher in proliferative than secretory phase endometrium (P < 0.001). The K2P channel blockers methanandamide, lidocaine, zinc and curcumin had antiproliferative effects (P < 0.01) in an endometrial epithelial cancer cell line indicating a role for TASK and TREK-1 channels in proliferation. Tetraethylammonium- and 4-aminopyridine-insensitive outwards currents were inhibited at all voltages by reducing extracellular pH from 7.4 to 6.6. Higher expression of TREK-1 expression in proliferative phase endometrium may, in part, underlie linked to increased cell division. The effects of pH and a lack of effect of non-specific channel blockers of voltage-gated potassium channels imply a role for K2P channels in the regulation of human endometrial function.

Highlights

The adult human endometrium is central to reproductive success undergoing monthly cyclical renewal in preparation for implantation
Immunohistochemistry of endometrial tissue sections obtained at various stages of the menstrual cycle expressed the epithelial cell marker E-cadherin in glands of both proliferative (n = 8) and secretory phase (n = 6) endometrium with respective representative images presented in Figure 1A and 1B
A variety of K2P channel subtypes was expressed in both Ishikawa cells (Fig. 2) and tissue biopsies of human endometrium obtained throughout the proliferative (n = 9) and secretory phases (n = 7) of the menstrual cycle (Fig. 3)

Summary

Introduction

The adult human endometrium is central to reproductive success undergoing monthly cyclical renewal in preparation for implantation. Progesterone converts the epithelium to a secretory phenotype, endometrial proliferation ceases and a transient receptive state, ‘the window of implantation’, is induced. During this brief period, electrolyte balance of the intrauterine fluid is crucial in ensuring apposition and attachment of the blastocyst to the luminal epithelium. The ionic composition of intrauterine fluid differs from normal serum in having a higher potassium (K+) concentration [2] and is supported by evidence from in vitro ion measurements in supernatants from cultured human endometrial epithelium [3]. Critical aspects of fertilization, implantation and early pregnancy are dependent on an appropriate ionic microenvironment which is in part determined by ion channel activity

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