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N‐ and c‐terminal extensions of μ‐conotoxins increase potency and selectivity for neuronal sodium channels
Author(s) -
Schroeder Christina I.,
Adams Denise,
Thomas Linda,
Alewood Paul F.,
Lewis Richard J.
Publication year - 2012
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22032
Subject(s) - sodium channel , chemistry , conotoxin , selectivity , peptide , sodium , potency , tetrodotoxin , biophysics , stereochemistry , biochemistry , in vitro , biology , catalysis , organic chemistry
μ‐Conotoxins are peptide blockers of voltage‐gated sodium channels (sodium channels), inhibiting tetrodotoxin‐sensitive neuronal (Na v 1.2) and skeletal (Na v 1.4) subtypes with highest affinity. Structure‐activity relationship studies of μ‐conotoxins SIIIA, TIIIA, and KIIIA have shown that it is mainly the C‐terminal part of the three‐loop peptide that is involved in binding to the sodium channel. In this study, we characterize the effect of N‐ and C‐terminal extensions of μ‐conotoxins SIIIA, SIIIB, and TIIIA on their potency and selectivity for neuronal versus muscle sodium channels. Interestingly, extending the N‐ or C‐terminal of the peptide by introducing neutral, positive, and/or negatively charged residues, the selectivity of the native peptide can be altered from neuronal to skeletal and the other way around. The results from this study provide further insight into the binding profile of μ‐conotoxins at voltage‐gated sodium channels, revealing that binding interactions outside the cysteine‐stablilized loops can contribute to μ‐conotoxin affinity and sodium channel selectivity. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 161–165, 2012.