Inhibition of cardiac HERG potassium channels by antidepressant maprotiline.
Eur J Pharmacol
; 531(1-3): 1-8, 2006 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-16423345
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antidepressivos de Segunda Geração
/
Canais de Potássio Éter-A-Go-Go
/
Maprotilina
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
México
País de publicação:
Holanda