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

Conor Mccloskey,David Tickle,Srinivasan Kanumilli,Samantha Mccavera,Jie Zhang,Nan Lin,Jolene Atia,Steve Thornton,Anatoly Shmygol,Elizabeth Bailey,Roberto Catalano,Yi‐Wah Chan,Timothy Dale,Manu Vatish,Pamela Brown,Cara C Rada ,Siobhán Quenby ,Derek J Trezise ,D.a.j Rand ,Sarah K England ,Catherine A Kettleborough ,Jan J Brosens ,Michael J Taggart ,Jeffrey C Jerman ,Hugo Van Den Berg ,Paul D Wright ,Jerod S Denton ,Andrew M Blanks

doi: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.

Highlights

Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage
Kcnj13 transcript levels increased markedly in the pregnant mouse uterus during mid-gestation, peaking on gestational day (GD) 15, and followed by a sharp decline towards term (C57BL/ 6J mice deliver in the morning of GD19; Fig 1A)
The important physiological roles of Kir channels are underscored by the many diseases that are associated with Kir channel malfunction, such as Bartter’s syndrome, Anderson syndrome, short Q-T syndrome and neonatal diabetes (Derst et al, 1997; Andelfinger et al, 2002; Edghill et al, 2004; Priori et al, 2005; Ellard et al, 2007)

Summary

Introduction

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. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. 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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