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Vol. 55, Issue 1, 134-141, January 1999
Department of Neurology and Neurosurgery, Montreal Neurological
Institute, McGill University, Montreal, Quebec, Canada
Voltage-gated sodium channels are inhibited by local anesthetic drugs.
This inhibition has complex voltage- and frequency-dependent properties, consistent with a model in which the sodium channel has low
affinity for local anesthetics when it is in resting states and higher
affinity when it is in open or inactivated states. Two residues, a
phenylalanine (F1710) and a tyrosine (Y1717), in transmembrane segment
IVS6 of the channel 
subunit are critical for state-dependent block.
We examined how these residues determine channel sensitivity to local
anesthetics by introducing mutations that varied their size,
hydrophobicity, and aromaticity. Block of resting channels by
tetracaine was correlated with hydrophobicity at position 1710, as if
hydrophobic drug-receptor interactions stabilize binding to resting
states. In contrast, drug action on open or inactivated channels
required an aromatic residue at this position. We propose that the
native phenylalanine at position 1710 stabilizes drug binding to open
or inactivated states by either cation-
or aromatic-aromatic
interactions between the aromatic side chain of the amino acid and
charged or aromatic moieties on the drug molecule. We also consider the
alternative possibility that mutations at this position affect drug
action by either altering access to the receptor or by allosteric
changes in receptor conformation. Mutations at position 1717 also
altered drug action; however, these effects were not well-correlated
with the size, hydrophobicity, or aromaticity of the substituted amino acid. These results suggest that the residue at this position does not
contribute directly to the drug receptor.
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