title: A role for two-pore potassium (K2P) channels in endometrial epithelial function.
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.
authors.affiliation: Academic Division of Obstetrics & Gynaecology, University of Nottingham, Derby, UK.
authors.forename: Suraj K
authors.initials: SK
authors.lastname: Patel
authors.forename: Leigh
authors.initials: L
authors.lastname: Jackson
authors.forename: Averil Y
authors.initials: AY
authors.lastname: Warren
authors.forename: Pratibha
authors.initials: P
authors.lastname: Arya
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shaw
authors.forename: Raheela N
authors.initials: RN
authors.lastname: Khan
mesh_terms: D000328:Adult; D001095:Arachidonic Acids / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials; D008597:Menstrual Cycle / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010060:Ovulation / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger; C103742:potassium channel protein TREK-1; C088155:methanandamide; C420132:potassium channel subfamily K member 3; D008012:Lidocaine; D003474:Curcumin