Referenced in: none

Automatically associated channels: Kv11.1

Title: Inhibition of cardiac HERG potassium channels by antidepressant maprotiline.

Authors: Tania Ferrer-Villada, Ricardo A Navarro-Polanco, Aldo A Rodríguez-Menchaca, Dora E Benavides-Haro, José A Sánchez-Chapula

Journal, date & volume: Eur. J. Pharmacol., 2006 Feb 15 , 531, 1-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16423345

Abstract
Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 microM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.