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]
- 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 YesInhibitorDetails Lidocaine Sodium channel protein type 5 subunit alpha Protein Humans YesInhibitorDetails Lidocaine Sodium channel protein type 9 subunit alpha Protein Humans YesInhibitorDetails