title: A point mutation at F1737 of the human Nav1.7 sodium channel decreases inhibition by local anesthetics.
abstract: Voltage-gated sodium channels (VGSC) contribute to the initiation and propagation of action potentials within the nervous system. These channels are important targets for inhibition by several classes of drugs, including antiarrhythmics and local anesthetics. Structural and pharmacological studies have localized the binding of these drugs to a common site near the channel's intracellular pore region. Point mutations within this region disrupt local anesthetic inhibition of cardiac, CNS, and skeletal muscle VGSC subtypes. This study was designed to test whether a similar structural requirement for drug binding exists on the peripheral neuronal VGSC subtype; Na(v)1.7. In support of this hypothesis, an alanine substitution for phenylalanine at position 1737 (F1737A) in the pore lining S6 segment of domain IV in human Na(v)1.7 reduced both use- and state- dependent inhibition of the local anesthetics, lidocaine and tetracaine, by 8-21-fold. We also saw a 2-3-fold reduction in tonic inhibition with the F1737A mutant. The voltage dependence of both activation and inactivation were unaffected by the F1737A mutation, however, fast inactivation kinetics were impaired, such that a significant portion of inward current remained at the end of a 20-ms depolarization. These data suggest that F1737 forms a part of the high affinity binding of local anesthetics as well as mediating inactivation processes of neuronal Na(v)1.7 channels.
authors.affiliation: Department of Pain/Migraine Research, Merck Research Laboratories, West Point, PA 19486, USA. jacqueline_panigel@merck.com
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Panigel
authors.forename: Sean Peter
authors.initials: SP
authors.lastname: Cook
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000779:Anesthetics, Local / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D017354:Point Mutation / Q000235:genetics*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D000779:Anesthetics, Local; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels