Kir7.1 is the physiological target for hormones and steroids that regulate uteroplacental function

Abstract

Preterm birth is a multifactorial syndrome that is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by the action of progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, but a nongenomic mode of action has long been suspected. Here we reveal that progesterone activates both human and murine inwardly rectifying potassium channel Kir7.1, which is expressed in mammalian myometrial smooth muscle and placental pericytes during late gestation. Kir7.1 is also activated by compounds used to prevent premature labor, including the progestogens 17-alpha-hydroxyprogesterone caproate and dydrogesterone, revealing an unexpected mode of action for these drugs. Our results reveal that Kir7.1 is the molecular target of a number of endogenous and synthetic steroids that control uterine excitability and placental function, and is therefore a promising therapeutic target to control utero-placental physiology and support healthy pregnancy.