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

Zhenhui Chen*, Boon-Hooi Ong¹, Nicholas G. Kambouris*, Eduardo Marbán², Gordon F. Tomaselli² and Jeffrey R. Balser¹

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

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