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Vol. 54, Issue 4, 733-739, October 1998
Department of Anesthesia Research Laboratories, Harvard Medical
School, Brigham and Women's Hospital, Boston, Massachusetts 02115 (S.N.W., G.K.W.), and
Department of Biology, State University of New
York at Albany, Albany, New York 12222 (S.-Y.W.)
Voltage-gated Na+ channels are a primary target for local
anesthetics (LAs). Open or inactivated Na+ channels usually
have a severalfold higher affinity for LAs than do resting channels.
Hille's modulated receptor hypothesis attributed the changes in LA
affinity to state-dependent alterations in the conformation of the LA
receptor. We expressed wild-type and mutant rat skeletal muscle (µ1)
Na+ channels in human embryonic kidney cells to investigate
the state-dependent modulation of LA receptor affinity. As an
alternative approach to using alanine for point mutation, we
substituted lysine (a hydrophilic residue) for native residues in the
putative LA receptor located in D4-S6 of the µ1 Na+
channel. Lysine mutation at Y1586 did not alter resting channel affinity for cocaine but did reduce resting affinity at F1579K and
N1584K by 2- and 3-fold, respectively. Compared with µ1, resting benzocaine block did not change at F1579K, decreased at N1584K, and
increased at Y1586K. These effects on resting block could largely be
accounted for by either steric/charge interference or cation-
electron interactions between particular moieties on the LA and lysine.
Surprisingly, lysine substitution at these residues allowed the
channels to undergo steady state fast inactivation yet reduced
inactivated channel block by cocaine by up to 27-fold and reduced the
benzocaine-induced leftward shift in the h
curve by up
to 22 mV. Our data suggest that transitions in channel state indeed
invoke conformational changes in the LA receptor and that lysine
mutations in the LA receptor region alter such conformational changes
during the transition to the inactivated state.
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