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Vol. 54, Issue 2, 389-396, August 1998
Department of Anesthesia, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts 02115 (G.-K.W., C.Q.), and
Department of Biological Sciences, State University of New York at
Albany, Albany, New York 12222 (S.-Y.W.)
Local anesthetics (LAs) are noncompetitive antagonists of batrachotoxin
(BTX) in voltage-gated Na+ channels. The putative LA
receptor has been delineated within the transmembrane segment S6 in
domain IV of voltage-gated Na+ channels, whereas the
putative BTX receptor is within segment S6 in domain I. In this study,
we created BTX-resistant muscle Na+ channels at segment
I-S6 (µ1-N434K, µ1-L437K) to test whether these residues modulate
LA binding. These mutant channels were expressed in transiently
transfected human embryonic kidney 293T cells, and their sensitivity to
lidocaine, QX-314, etidocaine, and benzocaine was assayed under
whole-cell, voltage-clamp conditions. Our results show that LA binding
in BTX-resistant µ1 Na+ channels was reduced
significantly. At 
100 mV holding potential, the reduction in LA
affinity was maximal for QX-314 (by 17-fold) and much less for neutral
benzocaine (by 2-fold). Furthermore, this reduction was residue
specific; substitution of positively charged lysine with negatively
charged aspartic acid (µ1-N434D) restored or even enhanced the LA
affinity. We conclude that µ1-N434K and µ1-L437K residues located
near the middle of the I-S6 segment of Na+ channels can
reduce the LA binding affinity without BTX. Thus, this reduction of the
LA affinity by point mutations at the BTX binding site is not caused by
gating changes induced by BTX alone. We surmise that the BTX receptor
and the LA receptor within segments I-S6 and IV-S6, respectively, may
align near or within the Na+ permeation pathway.
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