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

Christopher A Ahern; Amy L Eastwood; Dennis A Dougherty; Richard Horn

doi:10.4161/chan.2.1.6007

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

Journal article

Open access

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

Christopher A Ahern, Amy L Eastwood, Dennis A Dougherty and Richard Horn

Channels (Austin, Tex.), Vol.2(1), pp.1-3

01/2008

DOI: 10.4161/chan.2.1.6007

PMID: 18690056

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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 (Na(V) numbering) in the pore lining S6 segment of domain four (DIVS6) can abolish inactivated state inhibition.(1,2) 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.(3) What follows is a self guided tour of our motivation and experimental findings.

Ligands

Mutation

Models, Chemical

Anti-Arrhythmia Agents - pharmacology

Humans

Molecular Conformation

Muscle, Skeletal - metabolism

Sodium Channels - physiology

Static Electricity

Anesthetics, Local - pharmacology

Sodium Channels - chemistry

Models, Biological

Cations

Binding Sites

Hydrogen-Ion Concentration

Details

Title: Subtitle: New insights into the therapeutic inhibition of voltage-gated sodium channels
Creators: Christopher A Ahern - Department of Anesthesiology, University of British Columbia, Vancouver, British Columbia, Canada. Christopher.Ahern@UBC.ca
Amy L Eastwood
Dennis A Dougherty
Richard Horn
Resource Type: Journal article
Publication Details: Channels (Austin, Tex.), Vol.2(1), pp.1-3
Publisher: United States
DOI: 10.4161/chan.2.1.6007
PMID: 18690056
ISSN: 1933-6950
eISSN: 1933-6969
Language: English
Date published: 01/2008
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984070295602771

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