![]() Although the isoform differences in local anesthetic affinity seem to be less than in toxin affinity ( Fozzard and Hanck, 1996), understanding the molecular mechanisms of isoform differences in affinities may contribute to rational design of isoform-selective and safer Na + channel blockers.Įlucidating the mechanisms of state-dependent block by local anesthetics is obviously important. On the other hand, mexiletine caused more blocking for Na v1.5 than Na v1.2 or Na v1.4 by increasing the proportion of inactivated channels in Na v1.5 ( Kawagoe et al., 2002). It has been previously reported that the affinity of mexiletine for the inactivated channel is 2-fold higher in Na v1.5 than in Na v1.2 ( Weiser et al., 1999) and Na v1.5 is more sensitive to use-dependent block by mexiletine than Na v1.7 ( Wang et al., 2015). Affinity is known to vary as a function of the sodium channel gating state. Although mexiletine blocks various channel isoforms, there have been few reports on isoform differences in affinities of mexiletine. Mexiletine is an analog of the local anesthetic lidocaine and exerts its therapeutic action through blockade of voltage-gated Na + channels. In addition, mexiletine is clinically useful to relieve neuropathic pain ( Chabal et al., 1992) and protects brain neurons from injury in the models of ischemia ( Stys and Lesiuk, 1996). Mexiletine, a class Ib antiarrhythmic drug, is considered the first line for treating myotonic syndromes ( Jackson et al., 1994 Hudson et al., 1995 Camerino et al., 2007). Mexiletine at upper locations in the open state may effectively cause an electrostatic mechanism of block. These results provide crucial information on the mechanism of isoform differences in state-dependent block by local anesthetics and related drugs. High-affinity binding of mexiletine in the open states of Na v1.4 and Na v1.5 was caused by a π– π interaction with Phe, whereas mexiletine was located away from Phe in the open state of Na v1.2. Mexiletine occurred in the upper part in the pore in the open state and lower in the closed state. In our homology modeling based on the bacterial Na + channel, mexiletine changed its location and orientation in the pore depending on the state of the channel, irrespective of the channel isoform. Mutational studies revealed that the largest affinity change was observed for an Ala substitution of Phe in domain IV S6. Three channel isoforms had similar affinities of mexiletine for the rested state, and Na v1.4 and Na v1.5 had similar affinities for the open and inactivated states, while Na v1.2 had lower affinity for these states than Na v1.4 and Na v1.5. We compared state-dependent affinities of mexiletine for Na v1.2, Na v1.4, and Na v1.5 and examined the effects of mutations of transmembrane segment S6 residues on mexiletine block of Na v1.5. In addition, mexiletine has neuroprotective effects in models of brain ischemia. Mexiletine is a class Ib antiarrhythmic drug and is also used clinically to reduce or prevent myotonia.
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