# Kir6.2 channel activity is regulated by interaction of transmembrane domains 1 and 2 through I167 in the bundle‐crossing gate

## TL;DR

This study shows how a specific mutation in a potassium channel affects its activity and how nearby regions interact to control this.

## Contribution

The study identifies how the I167 mutation in Kir6.2 channels increases open probability and how TM1 residues interact with I167 to regulate this.

## Key findings

- The I167L and I167F mutations in Kir6.2 increase channel open probability (P_o).
- A double mutation of I167L and F75A normalizes the increased P_o.
- I167 appears to stabilize the open state of Kir6.2 channels.

## Abstract

ATP‐sensitive potassium (KATP) channel in pancreatic β‐cells is composed of four pore‐forming inward rectifier potassium (Kir) 6.2 subunits and four regulatory sulfonylurea receptor (SUR) 1 subunits and regulate insulin secretion. Kir6.2 consists of a N‐terminal region, an outer transmembrane helix (TM1), an intramembrane region that functions as a potassium selectivity filter, an inner transmembrane helix (TM2) that forms a bundle‐crossing gate, and a C‐terminal cytoplasmic domain. Mutations in the Kir6.2 subunit can cause neonatal diabetes with severe neurological features (DEND syndrome). The DEND syndrome‐inducing I167L mutation of Kir6.2 increases the open probability (P
o) of the KATP channel. To investigate the gating mechanism impacted by this mutation in Kir6.2 alone, we used C‐terminus‐truncated Kir6.2 channels to ascertain the impact of I167 mutations on P
o in Kir6.2 channels in the absence of SUR1. We found that I167L and I167F mutations showed an increased P
o while the P
o of other mutations (I167A, I167V) were unchanged when compared to wild‐type channels. By mutating residues in TM1 (W68, L72, F75) that may interact with I167, we found that a double mutation of I167L and F75A normalized the P
o. These results would suggest that I167 may play an important role in stabilizing the open state of Kir6.2 channels.