title: The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy.
abstract: Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility.
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Conor
authors: C
authors: McCloskey
authors: Division of Basic Science Research, Department of Obstetrics and Gynecology, School of Medicine Washington University in St. Louis,, St. Louis, MO, USA.
authors: Cara
authors: C
authors: Rada
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Elizabeth
authors: E
authors: Bailey
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Samantha
authors: S
authors: McCavera
authors: Warwick Systems Biology & Mathematics Institute University of Warwick, Coventry, UK.
authors: Hugo A
authors: HA
authors: van den Berg
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Jolene
authors: J
authors: Atia
authors: Warwick Systems Biology & Mathematics Institute University of Warwick, Coventry, UK.
authors: David A
authors: DA
authors: Rand
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Anatoly
authors: A
authors: Shmygol
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Yi-Wah
authors: YW
authors: Chan
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Siobhan
authors: S
authors: Quenby
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Jan J
authors: JJ
authors: Brosens
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Manu
authors: M
authors: Vatish
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
authors: Jie
authors: J
authors: Zhang
authors: Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health Vanderbilt University School of Medicine Medical Center North, Nashville, TN, USA.
authors: Jerod S
authors: JS
authors: Denton
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Michael J
authors: MJ
authors: Taggart
authors: Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK.
authors: Catherine
authors: C
authors: Kettleborough
authors: Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK.
authors: David
authors: D
authors: Tickle
authors: Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK.
authors: Jeff
authors: J
authors: Jerman
authors: Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK.
authors: Paul
authors: P
authors: Wright
authors: BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK.
authors: Timothy
authors: T
authors: Dale
authors: BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK.
authors: Srinivasan
authors: S
authors: Kanumilli
authors: BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK.
authors: Derek J
authors: DJ
authors: Trezise
authors: Exeter Medical School, Exeter, UK.
authors: Steve
authors: S
authors: Thornton
authors: MRC Centre for Reproductive Health (CRH), Queen's Medical Research Institute University of Edinburgh, Edinburgh, UK.
authors: Pamela
authors: P
authors: Brown
authors: MRC Centre for Reproductive Health (CRH), Queen's Medical Research Institute University of Edinburgh, Edinburgh, UK.
authors: Roberto
authors: R
authors: Catalano
authors: Department of Mathematics, Washington University, St. Louis, MO, USA.
authors: Nan
authors: N
authors: Lin
authors: Division of Basic Science Research, Department of Obstetrics and Gynecology, School of Medicine Washington University in St. Louis,, St. Louis, MO, USA.
authors: Sarah K
authors: SK
authors: England
authors: Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK andrew.blanks@warwick.ac.uk.
authors: Andrew M
authors: AM
authors: Blanks
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007743:Labor, Obstetric / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D014590:Uterine Contraction / Q000235:genetics / Q000378:metabolism*
chemical_list: C489477:Kir7.1 channel; D024661:Potassium Channels, Inwardly Rectifying
keywords: myometrium; parturition; potassium channels; pregnancy; uterus