Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1

Title: Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block.

Authors: Sridharan Rajamani, Corey L Anderson, Blake D Anson, Craig T January

Journal, date & volume: Circulation, 2002 Jun 18 , 105, 2830-5

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12070109

Abstract
Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K(+) current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K(+) current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results- We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximately 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block.Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.