A molecular basis for the different local anesthetic affinities of restingversus open and inactivated states of the sodium channel

Voltage-gated sodium channels are inhibited by local anesthetic drugs. This inhibition has complex voltage- and frequency-dependent properties, consis tent with a model in which the sodium channel has low affinity for local an esthetics when it is in vesting states and higher affinity when it is in op en or inactivated states. Two residues, a phenylalanine (F1710) and a tyros ine (Y1717), in transmembrane segment IVS6 of the channel a subunit are cri tical for state-dependent block. We examined how these residues determine c hannel sensitivity to local anesthetics by introducing mutations that varie d their size, hydrophobicity, and aromaticity. Block of vesting channels by tetracaine was correlated with hydrophobicity at position 1710, as if hydr ophobic 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 posit ion 1710 stabilizes drug binding to open or inactivated states by either ca tion-pi or aromatic-aromatic interactions between the aromatic side chain o f the amino acid and charged or aromatic moieties on the drug molecule. We also consider the alternative possibility that mutations at this position a ffect drug action by either altering access to the receptor or by allosteri c 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 resul ts suggest that the residue at this position does not contribute directly t o the drug receptor.