Preferred mexiletine block of human sodium channels with IVS4 mutations and its pH-dependence.
The effects of extracellular pH (6.2, 7.4 and 8.2) and 0.1 mM mexiletine, a channel blocker of the lidocaine type, are studied on two mutations of the fourth voltage sensor of the Nav1.4 sodium channel, R1448H/C. The fast inactivated channel state to which mexiletine preferentially binds is destabilized by the mutations. By contrast to the expected low response of R1448H/C carriers, mexiletine is particularly effective in preventing exercise-induced stiffness and paralysis from which these patients suffer. Our measurements performed in the whole-cell mode on stably transfected HEK cells show for the first time that the mutations strikingly accelerate closed-state inactivation and, as steady-state fast inactivation is shifted to more negative potentials, stabilize the fast inactivated channel state in the potential range around the resting potential. At pH 7.4 and 8.2, the phasic mexiletine block is larger for R1448C (55%) and R1448H (47%) than for wild-type channels (31%) due to slowed recovery from block (tau is approximately 520 ms for R1448C versus 270 ms for wild-type at pH 7.4) although the recovery from inactivation is slightly faster for the mutants (tau is approximately 1.9 ms for R1448C versus 3.8 ms for wild-type at pH 7.4). At pH 6.2, recovery from block is relatively fast (tau is approximately 35 ms for R1448H/C and 14 ms for wild-type) and thus shows no use-dependence. We conclude that enhanced closed-state inactivation expands the concept of a mutation-induced uncoupling of channel inactivation from activation to a new potential range and that the higher mexiletine efficacy in R1448H/C carriers compared to other myotonic patients offers a pharmacogenetic strategy for mutation-specific treatment.
Mohammadi
Bahram
B
Department of Neurology, Medical School Hannover, Hannover, Germany.
Jurkat-Rott
Karin
K
Alekov
Alexi
A
Dengler
Reinhard
R
Bufler
Johannes
J
Lehmann-Horn
Frank
F
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D003545:Cysteine / Q000235:genetics; D015444:Exercise; D006639:Histidine / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008801:Mexiletine / Q000494:pharmacology*; D009154:Mutation; D020967:Myotonic Disorders / Q000188:drug therapy / Q000378:metabolism; D010243:Paralysis; D018408:Patch-Clamp Techniques; D010597:Pharmacogenetics / Q000379:methods; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D008801:Mexiletine; D006639:Histidine; D003545:Cysteine