Lidocaine induces a slow inactivated state in rat skeletal muscle sodium channels

• Published in: The Journal of physiology 2000-04, Vol.524 (1), p.37-49
• Main Authors: Chen, Z, Ong, B H, Kambouris, N G, Marbán, E, Tomaselli, G F, Balser, J R
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Cell Line; Female; Humans; Kinetics; Lidocaine - pharmacology; Membrane Potentials - drug effects; Muscle, Skeletal - physiology; Mutagenesis, Site-Directed; Oocytes; Original; Protein Conformation - drug effects; Protein Structure, Secondary; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sodium - pharmacology; Sodium Channels - chemistry; Sodium Channels - drug effects; Sodium Channels - physiology; Transfection; Xenopus laevis
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.2000.t01-1-00037.x

Local anaesthetics such as lidocaine (lignocaine) interact with sodium channels in a manner that is exquisitely sensitive to the voltage-dependent conformational state of the ion channel. When depolarized in the presence of lidocaine, sodium channels assume a long-lived quiescent state. Although studies over the last decade have localized the lidocaine receptor to the inner aspect of the aqueous pore, the mechanistic basis of depolarization-induced ‘use-dependent’ lidocaine block remains uncertain. Recent studies have shown that lowering the extracellular Na + concentration ([Na + ] o ) and mutations in the sodium channel outer P-loop modulate occupancy of a quiescent ‘slow’ inactivated state with intermediate kinetics (termed I M ) that involves structural rearrangements in the outer pore. Site-directed mutagenesis and ion-replacement experiments were performed using voltage-clamped Xenopus oocytes and cultured (HEK-293) cells expressing wild-type and mutant rat skeletal muscle (μ1) sodium channels. Our results show that lowering [Na + ] o potentiates use-dependent lidocaine block. The effect of [Na + ] o is maintained despite a III-IV linker mutation that partially disrupts fast inactivation (F1304Q). In contrast, the effect of lowering [Na + ] o on lidocaine block is reduced by a P-loop mutation (W402A) that limits occupancy of I M . Our findings are consistent with a simple allosteric model where lidocaine binding induces channels to occupy a native slow inactivated state that is inhibited by [Na + ] o .