Potential role of the membrane in hERG channel functioning and drug-induced long QT syndrome

Autor: Étienne Chartrand, Alexandre A. Arnold, Isabelle Marcotte, Sarah Jenna, Andrée E. Gravel
Rok vydání: 2010
Předmět:
Drug
Magnetic Resonance Spectroscopy
Protein Conformation
media_common.quotation_subject
Long QT syndrome
Molecular Sequence Data
hERG
Biophysics
Pharmacology
010402 general chemistry
01 natural sciences
Biochemistry
Sudden cardiac death
Cell membrane
03 medical and health sciences
NMR spectroscopy
Transcriptional Regulator ERG
medicine
Extracellular
Humans
Voltage-gated potassium channel
Amino Acid Sequence
cardiovascular diseases
Bicelles
030304 developmental biology
media_common
0303 health sciences
Cardiotoxic drugs
biology
Chemistry
Circular Dichroism
Cell Membrane
Membrane-protein interaction
Cell Biology
medicine.disease
Potassium channel
0104 chemical sciences
3. Good health
Long QT Syndrome
medicine.anatomical_structure
Trans-Activators
cardiovascular system
biology.protein
Drug–protein interaction
Zdroj: Biochimica et Biophysica Acta (BBA) - Biomembranes. 1798:1651-1662
ISSN: 0005-2736
Popis: The human ether-à-go-go related gene (hERG) potassium channels are located in the myocardium cell membrane where they ensure normal cardiac activity. The binding of drugs to this channel, a side effect known as drug-induced (acquired) long QT syndrome (ALQTS), can lead to arrhythmia or sudden cardiac death. The hERG channel is a unique member of the family of voltage-gated K+ channels because of the long extracellular loop connecting its transmembrane S5 helix to the pore helix in the pore domain. Considering the proximal position of the S5-P linker to the membrane surface, we have investigated the interaction of its central segment I(583)-Y(597) with bicelles. Liquid and solid-state NMR experiments as well as circular dichroism results show a strong affinity of the I(583)-Y(597) segment for the membrane where it would sit on the surface with no defined secondary structure. A structural dependence of this segment on model membrane composition was observed. A helical conformation is favoured in detergent micelles and in the presence of negative charges. Our results suggest that the interaction of the S5-P linker with the membrane could participate in the stabilization of transient channel conformations, but helix formation would be triggered by interactions with other hERG domains. Because potential drug binding sites on the S5-P linker have been identified, we have explored the role of this segment in ALQTS. Four LQTS-liable drugs were studied which showed more affinity for the membrane than this hERG segment. Our results, therefore, identify two possible roles for the membrane in channel functioning and ALQTS.
Databáze: OpenAIRE
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