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Vol. 56, Issue 2, 404-413, August 1999
Department of Anesthesia Research Laboratories, Brigham and
Women's Hospital, Harvard Medical School, Boston,
Massachusetts (C.N., G.R.S, G.K.W.), and Department of Biological
Sciences, State University of New York at Albany, Albany, New York
(S.-Y.W.)
Voltage-gated Na+ channels are the primary targets of
local anesthetics (LAs). Amino acid residues in domain 4, transmembrane segment 6 (D4-S6) form part of the LA binding site. LAs inhibit binding
of the neurotoxin batrachotoxin (BTX). Parts of the BTX binding site
are located in D1-S6 and D4-S6. The affinity of BTX-resistant Na+ channels mutated in D1-S6 (µ1-N434K, µ1-N437K)
toward several LAs is significantly decreased. We have studied how
residue µ1-N434 influences LA binding. By using site-directed
mutagenesis, we created mutations at µ1-N434 that vary the
hydrophobicity, aromaticity, polarity, and charge and investigated
their influence on state-dependent binding and stereoselectivity of
bupivacaine. Wild-type and mutant channels were transiently expressed
in human embryonic kidney 293t cells and investigated under
whole-cell voltage-clamp. For resting channels, bupivacaine enantiomers
showed a higher potency in all mutant channels compared with wild-type
channels. These changes were not well correlated with the physical
properties of the substituted residues. Stereoselectivity was small and
almost unchanged. In inactivated channels, the potency of bupivacaine was increased in mutations containing a quadrupole of an aromatic group
(µ1-N434F, µ1-N434W, µ1-N434Y), a polar group (µ1-N434C), or a
negative charge (µ1-N434D) and was decreased in a mutation containing
a positive charge (µ1-N434K). In mutation µ1-N434R, containing the
positively charged arginine, the potency of S(
)-bupivacaine was
selectively decreased, resulting in a stereoselectivity (stereopotency ratio) of 3. Similar results were observed with cocaine but not with RAC 109 enantiomers. We propose that in inactivated channels, residue µ1-N434 interacts directly with the positively charged moiety
of LAs and that D1-S6 and D4-S6 form a domain-interface site for
binding of BTX and LAs in close proximity.
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