Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 9, Pages 1161-1174Publisher
WILEY-BLACKWELL
DOI: 10.15252/emmm.201403944
Keywords
pregnancy; parturition; potassium channels; uterus; myometrium
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Funding
- Biomedical Research Unit of Warwick Medical School
- University Hospitals Coventry and Warwickshire
- Medical Research Council [G0901801]
- capacity building studentship
- Action Medical Research [SP4507]
- National Institute of Health [R01 HD-037831]
- March of Dimes [21-FY12-133]
- EPSRC [EP/C544587/1] Funding Source: UKRI
- MRC [G0901801] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/C544587/1] Funding Source: researchfish
- Medical Research Council [G0901801] Funding Source: researchfish
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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.
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