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Vol. 59, Issue 5, 1100-1107, May 2001
Department of Biology, State University of New York at Albany,
Albany, New York (S.-Y.W.); and Department of Anesthesia, Harvard
Medical School and Brigham & Women's Hospital, Boston, Massachusetts
(M.B., G.K.W.)
Batrachotoxin (BTX) stabilizes the voltage-gated Na+
channels in their open conformation, whereas local anesthetics (LAs)
block Na+ conductance. Site-directed mutagenesis has
identified clusters of common residues at D1-S6, D3-S6, and D4-S6
segments within the 
-subunit Na+ channel that are
critical for binding of these two types of ligands. In this report, we
address whether segment D2-S6 is similarly involved in both BTX and LA
actions. Thirteen amino acid positions from G783 to L795 of the rat
skeletal muscle Na+ channel (µ1/Skm1) were individually
substituted with a lysine residue. Four mutants (N784K, L785K, V787K,
and L788K) expressed sufficient Na+ currents for further
studies. Activation and/or inactivation gating was altered in mutant
channels; in particular, µ1-V787K displays enhanced slow inactivation
and exhibited use-dependent inhibition of peak Na+ currents
during repetitive pulses. Two of these four mutants, µ1-N784K and
µ1-L788K, were completely resistant to 5 µM BTX. This BTX-resistant
phenotype could be caused by structural perturbations induced by a
lysine point mutation in the D2-S6 segment. However, these two
BTX-resistant mutants remained quite sensitive to bupivacaine block
with affinity for inactivated Na+ channels
(KI) of ~10 µM or less, which suggests
that µ1-N784 and µ1-L788 residues are not in close proximity to the
LA binding site.
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