Local anesthetics disrupt energetic coupling between the voltage-sensing segments of a sodium channel.

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Muroi Y, Chanda B

Local anesthetics disrupt energetic coupling between the voltage-sensing segments of a sodium channel.

J Gen Physiol. 2009 Jan;133(1):1-15. doi: 10.1085/jgp.200810103. Epub 2008 Dec 15.

PubMed ID

19088384 [ View in PubMed

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Abstract

Local anesthetics block sodium channels in a state-dependent fashion, binding with higher affinity to open and/or inactivated states. Gating current measurements show that local anesthetics immobilize a fraction of the gating charge, suggesting that the movement of voltage sensors is modified when a local anesthetic binds to the pore of the sodium channel. Here, using voltage clamp fluorescence measurements, we provide a quantitative description of the effect of local anesthetics on the steady-state behavior of the voltage-sensing segments of a sodium channel. Lidocaine and QX-314 shifted the midpoints of the fluorescence-voltage (F-V) curves of S4 domain III in the hyperpolarizing direction by 57 and 65 mV, respectively. A single mutation in the S6 of domain IV (F1579A), a site critical for local anesthetic block, abolished the effect of QX-314 on the voltage sensor of domain III. Both local anesthetics modestly shifted the F-V relationships of S4 domain IV toward hyperpolarized potentials. In contrast, the F-V curve of the S4 domain I was shifted by 11 mV in the depolarizing direction upon QX-314 binding. These antagonistic effects of the local anesthetic indicate that the drug modifies the coupling between the voltage-sensing domains of the sodium channel. Our findings suggest a novel role of local anesthetics in modulating the gating apparatus of the sodium channel.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Lidocaine	Sodium channel protein type 10 subunit alpha	Protein	Humans	Yes	Inhibitor	Details
Lidocaine	Sodium channel protein type 5 subunit alpha	Protein	Humans	Yes	Inhibitor	Details
Lidocaine	Sodium channel protein type 9 subunit alpha	Protein	Humans	Yes	Inhibitor	Details