State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone

Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure–function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pha...

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Bibliographic Details
Published in:Pflügers Archiv 2024-03, Vol.476 (3), p.323-335
Main Authors: Gomez-Lagunas, F., Barriga-Montoya, C., Pardo, J. P.
Format: Article
Language:English
Subjects:
Amiodarone
Amiodarone - pharmacology
Anti-Arrhythmia Agents - pharmacology
Antiarrhythmics
Biomedical and Life Sciences
Biomedicine
Cell Biology
Competition
Data analysis
Ectopic expression
Ether-A-Go-Go Potassium Channels - metabolism
Human Physiology
Humans
Hydrophobicity
Ion Channels
Ion Channels, Receptors and Transporters
Metabolism
Metabolites
Molecular Medicine
Neoplasms
Neurosciences
Physiology
Potassium channels (voltage-gated)
Receptors
Receptors and Transporters
Structure-function relationships
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Summary:Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure–function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.
ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-023-02893-x