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The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy
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(2014) The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy. EMBO Molecular Medicine, Volume 6 (Number 9). pp. 1161-1174. doi:10.15252/emmm.201403944 ISSN 1757-4676.
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Official URL: http://dx.doi.org/10.15252/emmm.201403944
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.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Mathematics Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Uterus -- Physiology, Pregnancy, Potassium channels | ||||||||
| Journal or Publication Title: | EMBO Molecular Medicine | ||||||||
| Publisher: | Wiley-Blackwell Publishing Ltd. | ||||||||
| ISSN: | 1757-4676 | ||||||||
| Official Date: | 23 July 2014 | ||||||||
| Dates: |
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| Volume: | Volume 6 | ||||||||
| Number: | Number 9 | ||||||||
| Page Range: | pp. 1161-1174 | ||||||||
| DOI: | 10.15252/emmm.201403944 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
| Date of first compliant deposit: | 28 December 2015 | ||||||||
| Date of first compliant Open Access: | 28 December 2015 | ||||||||
| Funder: | Warwick Medical School, University Hospitals Coventry and Warwickshire NHS Trust, Medical Research Council (Great Britain) (MRC), Action Medical Research (AMR), National Institutes of Health (U.S.) (NIH), March of Dimes Birth Defects Foundation | ||||||||
| Grant number: | G0901801 (MRC), SP4507 (AMR), R01 HD-037831 (NIH), 21-FY12-133 (MoD) |
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