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

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.

Focus on Kir7.1: physiology and channelopathy

“…Why does Kir7.1 channelopathy have only a retinal phenotype? 69 Within the eye Kir7.1 is also localized to other cell types, yet the phenotype is specific to RPE. How does an RPE apical membrane ion-channel defect generate ERG phenotype, signature of retina electrical output in response to light exposure?…”

Why the heart is like an orchestra and the uterus is like a soccer crowd

“…For example, the expression of many types of potassium channels vary as pregnancy progresses, which modulates myocyte excitability and action potential duration. [28][29][30] These events combine at the end of pregnancy to dramatically increase the connectivity of myometrial myocytes, which makes them more likely …”

Glial and neuronal expression of the Inward Rectifying Potassium Channel Kir7.1 in the adult mouse brain

“…In addition, Kir7.1 have been shown to control the excitability of uterine smooth muscle during pregnancy in mice (McCloskey et al. ). In the central nervous system (CNS), Kir7.1 have been identified in cerebellar Purkinje neurones and hippocampal pyramidal neurones (Krapivinsky et al.…”