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-Conotoxin MII on 3
2
Neuronal Nicotinic Receptors
Department of Molecular and Cellular Pharmacology, University of
Miami School of Medicine, Miami, Florida 33101 (S.C.H., F.N.M.,
C.W.L.), and Departments of
Biology (J.M.M., G.E.C.) and
Psychiatry
(J.M.M.), University of Utah, Salt Lake City, Utah 84112
The competitive antagonist 
-conotoxin-MII (-CTx-MII) is highly
selective for the 3
2 neuronal nicotinic receptor. Other receptor
subunit combinations (22, 42, 34) are >200-fold less
sensitive to blockade by this toxin. Using chimeric and mutant subunits, we identified amino acid residues of 3 and 2 that participate in determination of -CTx-MII sensitivity. Chimeric subunits, constructed from the 3 and 4 subunits, as well as from
the 3 and 2 subunits, were expressed in combination with the 2
subunit in Xenopus laevis oocytes. Chimeric subunits, formed from the 2 and 4 subunits, were expressed in
combination with 3. Determinants of -CTx-MII sensitivity on 3
were found to be within sequence segments 121-181 and 181-195. The
181-195 segment accounted for approximately half the difference in
toxin sensitivity between receptors formed by 2 and 3. When this
sequence of 2 was replaced with the corresponding 3 sequence, the
resulting chimera formed receptors only 26-fold less sensitive to
-CTx-MII than 32. Site-directed mutagenesis within segment
181-195 demonstrated that Lys185 and Ile188 are critical in
determination of sensitivity to toxin blockade. Determinants of
-CTx-MII sensitivity on 2 were mapped to sequence segments 1-54,
54-63, and 63-80. Site-directed mutagenesis within segment 54-63 of
2 demonstrated that Thr59 is important in determining -CTx-MII
sensitivity.
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