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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Differential interaction of R-mexiletine with the local anesthetic receptor site on brain and heart sodium channel alpha-subunits.

Mexiletine is a class I antiarrhythmic drug with neuroprotective effects in models of brain ischemia attributable to inhibition of brain sodium channels. We compared effects of R-mexiletine on wild-type and mutant rat brain (rbIIA) and heart (rh1) sodium channel alpha-subunits transiently expressed in tsA-201 cells. R-mexiletine induced tonic and frequency-dependent block and bound with a 26-fold (brain) or 35-fold (heart) higher affinity to inactivated sodium channels. Affinities of both resting and inactivated channels for R-mexiletine block were approximately 2-fold higher for heart than for brain channels. Mutations in transmembrane segment IVS6 of heart (rhF1762A) and brain (rbF1764A and rbY1771A) channels, which reduce block by other local anesthetics, reduced high-affinity block of inactivated channels and frequency-dependent block of open channels by R-mexiletine and abolished the difference in affinity between brain and heart sodium channels. Unlike previous local anesthetics studied, the strongest effect was observed for mutation rbY1771A. Comparison of mutations of the homologous phenylalanine residue in brain and heart channels showed striking differences in the effects of the mutations. rbF1764A reduced drug block by slowing R-mexiletine binding to inactivated channels, whereas rhF1762A reduced block by increasing the rate of dissociation from inactivated and resting channels. Thus, rbF1764/rhF1762 is a critical determinant of affinity and tissue-specific differences in mexiletine block of brain and heart sodium channels, but its role in drug interaction differs in these two channel isoforms.[1]


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