The epithelial potassium channel Kir7.1 is stimulated by progesterone

Abstract

The choroid plexus (CP) epithelium secretes cerebrospinal fluid and plays an important role in healthy homeostasis of the brain. CP function can be influenced by sex steroid hormones; however, the precise molecular mechanism of such regulation is not well understood. Here, using whole-cell patch-clamp recordings from male and female murine CP cells, we show that application of progesterone resulted in specific and strong potentiation of the inwardly rectifying potassium channel Kir7.1, an essential protein that is expressed in CP and is required for survival. The potentiation was progesterone specific and independent of other known progesterone receptors expressed in CP. This effect was recapitulated with recombinant Kir7.1, as well as with endogenous Kir7.1 expressed in the retinal pigment epithelium. Current-clamp studies further showed a progesterone-induced hyperpolarization of CP cells. Our results provide evidence of a progesterone-driven control of tissues in which Kir7.1 is present.

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

“…Recently, we reported that murine Kir7.1 expressed in the choroid plexus and retinal pigment epithelia is potently and specifically activated by progesterone (19,20) and that such activation is independent of G-protein regulation (20). This finding led us to compare the properties of human and murine Kir7.1 to verify whether human Kir7.1 can be regulated by progesterone in the similar manner.…”

Neurosteroid enantiomers as potentially novel neurotherapeutics

“…These receptors include a class of G-protein coupled receptors (GPCRs) called membrane progesterone receptors (mPRs) that activate intracellular signaling pathways akin to other GPCRs and have neuroprotective effects ( Thomas and Pang, 2020 ), and PGRMC1 (PROG receptor membrane component 1), receptors that activate cytochrome P450 enzymes, affect lipid metabolism and promote cell survival ( Bassani et al, 2022 ; Ghoumari et al, 2020 ; Gonzalez et al, 2020 ). PROG was recently shown to be a PAM of the voltage-gated potassium channel Kir7.1 in epithelial cells of the choroid plexus ( Bjorkgren et al, 2022 ). While it is unclear whether PROG directly modulates GABA A Rs, it is certain that some of its metabolites (e. g. AlloP and others) are highly effective and direct acting PAMs.…”

2022

“…The senior Cranefield Award, for someone at the start of their independent research career, has been awarded to Polina Lishko, from the University of California, Berkeley. Her work investigated the mechanism by which sex steroid hormones influence the choroid plexus and identified a role for progesterone in increasing an inwardly rectifying potassium current, Kir7.1 ( Björkgren et al, 2021 ).…”