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

C. McCloskey, Cara Rada, Elizabeth Bailey, Samantha McCavera, Jolene Atia, Anatoly Shmygol, Yi-Wah Chan, Siobhan Quenby, Jan Brosens, Manu Vatish, Jie Zhang, Jerod Denton, Michael Taggart, Catherine Kettleborough, David Tickle, Jeff Jerman, Paul Wright, Timothy Dale, Srinivasan Kanumilli, Derek Trezise & 8 others Steve Thornton, Pamela Brown, Roberto Catalano, Nan Lin, S. England, Andrew Blanks, D. A. Rand, H. A. van den Berg

    Research output: Contribution to journalArticle

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    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.
    Original languageEnglish
    Pages (from-to)61-74
    JournalEMBO Molecular Medicine
    Volume6
    Issue number9
    Early online date23 Jul 2014
    DOIs
    Publication statusPublished - Sep 2014

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    Inwardly Rectifying Potassium Channel
    Pregnancy
    Smooth Muscle
    Myometrium
    Potassium Channels
    Premature Birth
    MicroRNAs
    Muscle Cells
    Uterus
    Cell Membrane
    Genome
    Hemorrhage
    Pharmaceutical Preparations
    Therapeutics

    Bibliographical note

    Published under the terms of the CC BY 4.0 license

    Keywords

    • myometrium
    • parturition
    • potassium channels
    • pregnancy
    • uterus

    Cite this

    McCloskey, C., Rada, C., Bailey, E., McCavera, S., Atia, J., Shmygol, A., ... van den Berg, H. A. (2014). The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy. EMBO Molecular Medicine, 6(9), 61-74. https://doi.org/10.15252/emmm.201403944

    The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy. / McCloskey, C.; Rada, Cara; Bailey, Elizabeth; McCavera, Samantha; Atia, Jolene; Shmygol, Anatoly; Chan, Yi-Wah; Quenby, Siobhan; Brosens, Jan; Vatish, Manu; Zhang, Jie; Denton, Jerod; Taggart, Michael; Kettleborough, Catherine; Tickle, David; Jerman, Jeff; Wright, Paul; Dale, Timothy; Kanumilli, Srinivasan; Trezise, Derek; Thornton, Steve; Brown, Pamela; Catalano, Roberto; Lin, Nan; England, S.; Blanks, Andrew; Rand, D. A.; van den Berg, H. A.

    In: EMBO Molecular Medicine, Vol. 6, No. 9, 09.2014, p. 61-74.

    Research output: Contribution to journalArticle

    McCloskey, C, Rada, C, Bailey, E, McCavera, S, Atia, J, Shmygol, A, Chan, Y-W, Quenby, S, Brosens, J, Vatish, M, Zhang, J, Denton, J, Taggart, M, Kettleborough, C, Tickle, D, Jerman, J, Wright, P, Dale, T, Kanumilli, S, Trezise, D, Thornton, S, Brown, P, Catalano, R, Lin, N, England, S, Blanks, A, Rand, DA & van den Berg, HA 2014, 'The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy' EMBO Molecular Medicine, vol. 6, no. 9, pp. 61-74. https://doi.org/10.15252/emmm.201403944
    McCloskey, C. ; Rada, Cara ; Bailey, Elizabeth ; McCavera, Samantha ; Atia, Jolene ; Shmygol, Anatoly ; Chan, Yi-Wah ; Quenby, Siobhan ; Brosens, Jan ; Vatish, Manu ; Zhang, Jie ; Denton, Jerod ; Taggart, Michael ; Kettleborough, Catherine ; Tickle, David ; Jerman, Jeff ; Wright, Paul ; Dale, Timothy ; Kanumilli, Srinivasan ; Trezise, Derek ; Thornton, Steve ; Brown, Pamela ; Catalano, Roberto ; Lin, Nan ; England, S. ; Blanks, Andrew ; Rand, D. A. ; van den Berg, H. A. / The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy. In: EMBO Molecular Medicine. 2014 ; Vol. 6, No. 9. pp. 61-74.
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    AU - Atia, Jolene

    AU - Shmygol, Anatoly

    AU - Chan, Yi-Wah

    AU - Quenby, Siobhan

    AU - Brosens, Jan

    AU - Vatish, Manu

    AU - Zhang, Jie

    AU - Denton, Jerod

    AU - Taggart, Michael

    AU - Kettleborough, Catherine

    AU - Tickle, David

    AU - Jerman, Jeff

    AU - Wright, Paul

    AU - Dale, Timothy

    AU - Kanumilli, Srinivasan

    AU - Trezise, Derek

    AU - Thornton, Steve

    AU - Brown, Pamela

    AU - Catalano, Roberto

    AU - Lin, Nan

    AU - England, S.

    AU - Blanks, Andrew

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