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Vol. 56, Issue 6, 1238-1244, December 1999
-Subunits
Department of Pharmacology, University of Washington School of
Medicine, Seattle, Washington (T.W., Y.Q., W.A.C., T.S.); and
Department of Central Nervous System Research, Boehringer
Ingelheim Pharma KG, Ingelheim, Germany (T.W.)
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
-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.
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