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New insights into the therapeutic inhibition of voltage-gated sodium channels

Ahern, Christopher A. and Eastwood, Amy L. and Dougherty, Dennis A. and Horn, Richard (2008) New insights into the therapeutic inhibition of voltage-gated sodium channels. Channels, 2 (1). pp. 1-3. ISSN 1933-6950. https://resolver.caltech.edu/CaltechAUTHORS:20200415-141820540

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Abstract

Antiarrhythmics, anticonvulsants and local anesthetics inhibit voltage gated sodium channels and reduce membrane excitability in neurons and muscle, making them useful in the management of cardiac arrhythmias, epilepsy and pain. These compounds, which are often termed singly in the literature as ‘local anesthetics’, have at least two inhibitory states: a resting inhibition that develops with intermittent stimulation and a higher affinity inhibition that arises upon repeated depolarization and likely involves the inactivated state of the channel. Although elucidating their mechanism of inhibition has been an active area of research for decades, many questions remain unanswered. Do these two inhibitory states share a common, but guarded or modulated receptor? Or do they represent different protonated states of the drugs, many of which have pKa’s close to physiological pH, thereby yielding a significant population of both charged and uncharged compound inside cells. Some mechanistic clues can be found by mutating conserved phenylalanine and tyrosine residues of the ‘local anesthetic receptor’ in the channel’s inner vestibule. Mutations of these aromatic residues universally disrupt the mechanism of drug inhibition in numerous channel isoforms. For instance, non aromatic substitutions of Phe1579 (NaV1.4 numbering) in the pore lining S6 segment of domain four (DIVS6) can abolish inactivated state inhibition. The strict conservation of Phe1579 and other DIVS6 aromatic residues in all nine sodium channel isoforms led us to further dissect the role of this and other aromatic residues on local anesthetic inhibition. We recently employed subtly modified phenylalanine derivatives to better understand the role of these aromatics in the binding of local anesthetics and found a significant electrostatic interaction at one site, Phe1579, contributes to channel inhibition. What follows is a self guided tour of our motivation and experimental findings.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.4161/chan.2.1.6007DOIArticle
ORCID:
AuthorORCID
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2008 Landes Bioscience. Submitted: 04/01/08; Accepted: 04/01/08.
Subject Keywords:Local anesthetic, anti-arrhythmic, voltage-gated sodium channel, in vivo nonsense suppression, cation-π, ab initio
Issue or Number:1
Record Number:CaltechAUTHORS:20200415-141820540
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200415-141820540
Official Citation:Christopher Ahern, Amy Eastwood, Dennis Dougherty & Richard Horn (2008) New insights into the therapeutic inhibition of voltage-gated sodium channels, Channels, 2:1, 1-3, DOI: 10.4161/chan.2.1.6007
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102567
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Apr 2020 21:28
Last Modified:15 Apr 2020 21:28

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