PubMed 12618226

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNQ1 , Kv11.1 , Kv2.1 , Kv7.1

Title: [K(+)](o)-dependent change in conformation of the HERG1 long QT mutation N629D channel results in partial reversal of the in vitro disease phenotype.

Authors: Guo Qi Teng, James P Lees-Miller, Yanjun Duan, Bao-Tsen Li, Pin Li, Henry J Duff

Journal, date & volume: Cardiovasc. Res., 2003 Mar , 57, 642-50

PubMed link:

We hypothesized that exposure of N629D/wildtype channels to transient increases in [K(+)](o) could alter the conformation of the outer vestibule and thus reverse the disease phenotype. N629D is a recently described mutation of the HERG1 gene that causes familial long QT syndrome. This mutation alters the pore signature sequence resulting in loss of K(+) selectivity. Previous studies have reported that enforced occupancy of [K(+)](o) at sites near the selectivity filter alters the conformation/folding of the outer vestibule of the Kv2.1 channel.Since the long QT syndrome is manifest in individuals who are heterozygous for this HERG trait, we co-expressed N629D and the wildtype at equimolar concentrations.Co-expression of N629D/wildtype in Xenopus oocytes and mammalian cells resulted in a channel with a positive shift in reversal potential and a loss in the outward tail current, relative to the wildtype. Exposure of the N629D/wildtype to transient increases in [K(+)](o) from 5 to 40 mM/l changed the tail current from inward to outward during repolarization and restored the reversal potential to values similar to the wildtype. These findings in Xenopus oocytes were also seen when N620D/wildtype channels were expressed in mammalian cells. These [K(+)](o)-dependent changes persisted for hours after the [K(+)](o) was returned to 2.5 mM. This potential therapeutic effect began with increases in [K(+)](o) from 2.5 to 5 mM.This study reports a novel therapeutic strategy and mechanism to partially restore physiologic function in this HERG LQTS mutation.