# Bioactive lipid-mediated structural and functional regulation of the essential human potassium channel Kir7.1

## TL;DR

This paper reveals how bioactive lipids regulate the essential human potassium channel Kir7.1 using high-resolution structures and identifies potential drugs to modulate its function.

## Contribution

The study provides novel cryo-EM structures of Kir7.1 and identifies a steroid-binding site and cholesterol's inhibitory role in channel regulation.

## Key findings

- Cryo-EM structures of Kir7.1 reveal a steroid-binding site and how cholesterol inhibits the channel.
- Activating steroids work with PI4,5P2 to open the channel through structural changes.
- Electrophysiological data identify Kir7.1 activators with therapeutic potential.

## Abstract

The inwardly rectifying potassium channel Kir7.1 is essential for the physiological function of diverse tissues, including the retinal pigment epithelium and the gestational myometrium. Loss-of-function mutations in KCNJ13, which encodes Kir7.1, or conditional ablation of Kir7.1 in the retinal pigment epithelium, lead to early-onset vision loss. Despite strong genetic evidence supporting Kir7.1 as a therapeutic target, its regulation by endogenous ligands—beyond phosphoinositides—remains poorly understood. Here, we report cryo-electron microscopy structures of human Kir7.1 in multiple functional states at resolutions ranging from 2.8 Å to 4.0 Å. These structures uncover the molecular basis of Kir7.1 modulation by PI4,5P2, its selectivity, rectification, and identify a distinct steroid-binding site that may mediate cooperative channel gating. Our data suggest that endogenous cholesterol acts as an inhibitory ligand, which is displaced by select activating steroids. These activating steroids work in concert with PI4,5P2 to promote channel opening through profound changes in cytoplasmic domains, and the linker region. Electrophysiological analyses define a pharmacological landscape of Kir7.1 activators, providing innovative tools to probe and modulate channel function in both physiological and pathological contexts.

Kir7.1 is an essential potassium channel. The authors report cryo-EM structures in multiple states revealing how bioactive lipids modulate Kir7.1, and define a pharmacological landscape that identifies agonists with therapeutic potential.