Open AccessThe inwardly rectifying K + channel KIR 7.1 controls uterine excitability throughout pregnancy
Author(s) -
McCloskey Conor,
Rada Cara,
Bailey Elizabeth,
McCavera Samantha,
Berg Hugo A,
Atia Jolene,
Rand David A,
Shmygol Anatoly,
Chan YiWah,
Quenby Siobhan,
Brosens Jan J,
Vatish Manu,
Zhang Jie,
Denton Jerod S,
Taggart Michael J,
Kettleborough Catherine,
Tickle David,
Jerman Jeff,
Wright Paul,
Dale Timothy,
Kanumilli Srinivasan,
Trezise Derek J,
Thornton Steve,
Brown Pamela,
Catalano Roberto,
Lin Nan,
England Sarah K,
Blanks Andrew M
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201403944
Subject(s) - myometrium , contractility , uterotonic , uterine contraction , endocrinology , medicine , gene knockdown , uterus , myocyte , biology , cell culture , genetics , oxytocin
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 mi RNA 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 VU 590 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.