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J. Biol. Chem., Vol. 277, Issue 37, 33610-33615, September 13, 2002
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From the Departments of Many venomous organisms produce toxins that
disrupt neuromuscular communication to paralyze their prey. One common
class of such toxins comprises nicotinic acetylcholine receptor
antagonists (nAChRs). Thus, most toxins that act on nAChRs are targeted
to the neuromuscular subtype. The toxin characterized in this report, The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF526267.
-Conotoxin GIC from Conus geographus, a
Novel Peptide Antagonist of Nicotinic Acetylcholine Receptors*
§¶,
, Psychiatry,
§ Biology, and Pathology, University of Utah, Salt
Lake City, Utah 84112 and ** Cognetix, Inc., Salt Lake
City, Utah 84108
-conotoxin GIC, is a most striking exception. The 16-amino acid peptide was identified from a genomic DNA clone from Conus
geographus. The predicted mature toxin was synthesized, and
synthetic toxin was used in all studies described. -Conotoxin GIC
shows no paralytic activity in fish or mice. Furthermore, even at
concentrations up to 100 µM, the peptide has no
detectable effect on the human muscle nicotinic receptor subtype
heterologously expressed in Xenopus oocytes. In contrast,
the toxin has high affinity (IC50 
1.1 nM)
for the human 3
2 subunit combination, making it the most
neuronally selective nicotinic antagonist characterized thus far. Although -conotoxin GIC shares some sequence similarity with
-conotoxin MII, which is also a potent 32 nicotinic
antagonist, it is much less hydrophobic, and the kinetics of channel
block are substantially different. It is noteworthy that the
nicotinic ligands in C. geographus venom fit an emerging
pattern in venomous predators, with one nicotinic antagonist targeted
to the muscle subtype (thereby causing paralysis) and a second
nicotinic antagonist targeted to the 32 nAChR subtype (possibly
inhibiting the fight-or-flight response).
*
This work was supported by National Institutes of Health
Grants MH 53631 and GM 48677.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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