The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy

EMBO Molecular Medicine

Conor McCloskey⁵  Cara Rada¹  Elizabeth Bailey⁵  Samantha McCavera⁵  Hugo A van den Berg⁷  Jolene Atia⁵  David A Rand⁷  Anatoly Shmygol⁵  Yi-Wah Chan⁵  Siobhan Quenby⁵  Jan J Brosens⁵  Manu Vatish⁵  Jie Zhang⁵  Jerod S Denton⁶  Michael J Taggart¹⁰  Catherine Kettleborough³  David Tickle³  Jeff Jerman³  Paul Wright³  Timothy Dale⁸  Srinivasan Kanumilli⁸  Derek J Trezise⁸  Steve Thornton²  Pamela Brown⁴  Roberto Catalano⁴  Nan Lin^5,9  Sarah K England¹ 

[1] Division of Basic Science Research, Department of Obstetrics and Gynecology, School of Medicine, Washington University in St. Louis,, St. Louis, MO, USA;Exeter Medical School, Exeter, UK;Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK;MRC Centre for Reproductive Health (CRH), Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK;Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry, UK;Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health, Vanderbilt University School of Medicine, Medical Center North, Nashville, TN, USA;Warwick Systems Biology & Mathematics Institute, University of Warwick, Coventry, UK;BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK;Department of Mathematics, Washington University, St. Louis, MO, USA;Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

关键词: pregnancy;    parturition;    potassium channels;    uterus;    myometrium;   

DOI  :  10.15252/emmm.201403944

来源: Wiley

【 摘 要 】

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.

Synopsis

Only few effective treatments can manipulate uterine contractility for the prevention of dystocia, preterm labor or post-partum hemorrhage. This study reveals Kir7.1 channel as a potential target for increasing uterine contractions and identifies novel Kir7.1 inhibitors.

• A genome-wide scan of all known potassium channels combined with computational modeling identified Kir7.1 as a potentially useful therapeutic target.
• Kir7.1 expression increases in mid gestation and declines towards the onset of labor in mice and humans.
• Kir7.1 inhibition in vitro and in vivo increases uterine contractility.
• Novel inhibitors of Kir7.1 induce contractions of greater magnitude than a commonly used uterine stimulant oxytocin.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.