Inhibition of cardiac HERG potassium channels by antidepressant maprotiline.
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.
Ferrer-Villada
Tania
T
Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Apdo. Postal 199, C.P. 28000, Colima, Mexico.
Navarro-Polanco
Ricardo A
RA
Rodríguez-Menchaca
Aldo A
AA
Benavides-Haro
Dora E
DE
Sánchez-Chapula
José A
JA
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008376:Maprotiline / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017354:Point Mutation; D014981:Xenopus
D018687:Antidepressive Agents, Second-Generation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008376:Maprotiline