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EMBO Mol Med. 2014 Sep;6(9):1161-74. doi: 10.15252/emmm.201403944.

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

Author information

1
Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK.
2
Division of Basic Science Research, Department of Obstetrics and Gynecology, School of Medicine Washington University in St. Louis,, St. Louis, MO, USA.
3
Warwick Systems Biology & Mathematics Institute University of Warwick, Coventry, UK.
4
Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health Vanderbilt University School of Medicine Medical Center North, Nashville, TN, USA.
5
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
6
Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK.
7
BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK.
8
Exeter Medical School, Exeter, UK.
9
MRC Centre for Reproductive Health (CRH), Queen's Medical Research Institute University of Edinburgh, Edinburgh, UK.
10
Department of Mathematics, Washington University, St. Louis, MO, USA.
11
Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK andrew.blanks@warwick.ac.uk.

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.

KEYWORDS:

myometrium; parturition; potassium channels; pregnancy; uterus

PMID:
25056913
PMCID:
PMC4197863
DOI:
10.15252/emmm.201403944
[Indexed for MEDLINE]
Free PMC Article

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