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Vol. 56, Issue 2, 290-299, August 1999
Department of Neurobiology, Harvard Medical School, Boston,
Massachusetts
Tetracaine (N,N-dimethylaminoethyl-4-butylaminobenzoate) and
related N,N-dialkylaminoethyl substituted
benzoic acid esters have been used to characterize the high-affinity
binding site for aromatic amine noncompetitive antagonists in the
Torpedo nicotinic acetylcholine receptor (nAChR).
[3H]Tetracaine binds at equilibrium to a single site with
a Keq value of 0.5 µM in the absence of
agonist or presence of 
-bungarotoxin and with a
Keq value of 30 µM in the presence of
agonist (i.e., for nAChR in the desensitized state). Preferential
binding to nAChR in the absence of agonist is also seen for
N,N-DEAE and N,N-diethylaminopropyl esters, both
binding with 10-fold higher affinity in the absence of agonist than in
the presence, and for the 4-ethoxybenzoic acid ester of
N,N-diethylaminoethanol, but not for the
4-amino benzoate ester (procaine). Irradiation at 302 nm of nAChR-rich
membranes equilibrated with [3H]tetracaine resulted in
covalent incorporation with similar efficiency into nAChR , 
,
, and 
subunits. The pharmacological specificity of nAChR subunit
photolabeling as well as its dependence on [3H]tetracaine
concentration establish that the observed photolabeling is at the
high-affinity [3H]tetracaine-binding site. Within subunit, 
95% of specific photolabeling was contained within a
20-kilodalton proteolytic fragment beginning at Ser173 that
contains the M1 to M3 hydrophobic segments. With all four subunits
contributing to [3H]tetracaine site, the site in the
closed channel state of the nAChR is most likely within the central ion
channel domain.
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