T. Weiser et al., Differential interaction of R-mexiletine with the local anesthetic receptor site on brain and heart sodium channel alpha-subunits, MOLEC PHARM, 56(6), 1999, pp. 1238-1244
Mexiletine is a class I antiarrhythmic drug with neuroprotective effects in
models of brain ischemia attributable to inhibition of brain sodium channe
ls. 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 inac
tivated sodium channels. Affinities of both resting and inactivated channel
s for R-mexiletine block were approximately 2-fold higher for heart than fo
r brain channels. Mutations in transmembrane segment IVS6 of heart (rhF1762
A) 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 th
e difference in affinity between brain and heart sodium channels. Unlike pr
evious local anesthetics studied, the strongest effect was observed for mut
ation rbY1771A. Comparison of mutations of the homologous phenylalanine res
idue in brain and heart channels showed striking differences in the effects
of the mutations. rbF1764A reduced drug block by slowing R-mexiletine bind
ing to inactivated channels, whereas rhF1762A reduced block by increasing t
he rate of dissociation from inactivated and resting channels. Thus, rbF176
4/rhF1762 is a critical determinant of affinity and tissue-specific differe
nces in mexiletine block of brain and heart sodium channels, but its role i
n drug interaction differs in these two channel isoforms.