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Vol. 53, Issue 6, 1112-1119, June 1998
3 Subunit
Department of Molecular and Cellular Pharmacology, University of
Miami School of Medicine, Miami, Florida 33101
Neuronal bungarotoxin (NBT) is a highly selective, slowly reversible,
competitive antagonist of the 
3
2 neuronal nicotinic receptor.
Contributions to NBT sensitivity are made by both the 3 and 2
subunits. We used a chimeric subunit to demonstrate that the entire
3 contribution lies within sequence segment 84-215. Construction
and analysis of a series of mutant 3 subunits identified seven amino
acid residues (Thr143, Tyr184, Lys185, His186, Ile188, Gln198, Ser203)
within this region that contribute to NBT sensitivity. Changing Thr143
to lysine, as in 2, resulted in a ~1000-fold loss of NBT
sensitivity. The effect on NBT sensitivity of changing each of the
other six residues ranged from 1.8- to 40.5-fold. More extensive
mutagenesis demonstrated that Thr143 serves as part of the consensus
sequence for glycosylation at N141, and it is this glycosylation that
is the determinant of NBT sensitivity. Only serine could substitute for
threonine to maintain full NBT sensitivity, and changing Asn141 to
alanine resulted in a ~300-fold loss of NBT sensitivity. The chimera
2-181-3, containing all identified determinants except the
glycosylation site, formed receptors insensitive to 300 nM
NBT. Installation of threonine to complete the glycosylation consensus
site in this chimera conferred NBT sensitivity only 10-fold less than
that of wild-type 32. These seven determinants of NBT sensitivity
are located in close proximity to a series of conserved residues that
are common features of all nicotinic receptor binding sites.
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