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Lookup NU author(s): Professor Michael TaggartORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): McCloskey C, Rada C, Bailey E, McCavera S, van den Berg HA, Atia J, Rand DA, Shmygol A, Chan YW, Quenby S, Brosens JJ, Vatish M, Zhang J, Denton JS, Taggart MJ, Kettleborough C, Tickle D, Jerman J, Wright P, Dale T, Kanumilli S, Trezise DJ, Thornton S, Brown P, Catalano R, Lin N, England SK, Blanks AM
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2014
Volume: 6
Issue: 9
Pages: 1161-1174
Print publication date: 01/09/2014
Online publication date: 23/07/2014
Acceptance date: 02/07/2014
Date deposited: 07/11/2014
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: Wiley-Blackwell Publishing Ltd.
URL: http://dx.doi.org/10.15252/emmm.201403944
DOI: 10.15252/emmm.201403944
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