RT Journal Article
SR Electronic
T1 Molecular Determinants of Pentamidine-induced hERG Rrafficking Inhibition
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.075135
DO 10.1124/mol.111.075135
A1 Adrienne T Dennis
A1 Lu Wang
A1 Hanlin Wan
A1 Drew Nassal
A1 Isabelle Deschenes
A1 Eckhard Ficker
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/11/01/mol.111.075135.abstract
AB Pentamidine is an anti-protozoical compound that clinically causes acquired long QT syndrome which is associated with prolonged QT intervals, tachycardias and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by blocking cardiac inward rectifier currents acutely. At the same time, pentamidine reduces surface expression of the cardiac potassium channel IKr/hERG. This is unusual in that acLQTS is caused most often by direct block of the cardiac potassium current IKr/hERG. The present study was designed to provide a more complete picture of how hERG surface expression is disrupted by pentamidine at the cellular and molecular level. Using biochemical and electrophysiological methods we found that pentamidine exclusively inhibits hERG export from the endoplasmic reticulum to the cell surface in a heterologous expression system as well as in cardiomyocytes. hERG trafficking inhibition could be rescued in the presence of the pharmacological chaperone astemizole. We used rescue experiments in combination with an extensive mutational analysis to locate an interaction site for pentamidine at phenylalanine 656, a crucial residue in the canonical drug binding site of terminally folded hERG. Our data suggest that pentamidine binding to a folding intermediate of hERG arrests channel maturation in a conformational state that cannot be exported from the endoplasmic reticulum. We propose that pentamidine is the founding member of a novel pharmacological entity whose members act as small molecule 'anti-chaperones'.