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Research Article
N- and c-terminal extensions of μ-conotoxins increase potency and selectivity for neuronal sodium channels †
Article first published online: 10 FEB 2012
DOI: 10.1002/bip.22032
Copyright © 2012 Wiley Periodicals, Inc.
Additional Information
How to Cite
Schroeder, C. I., Adams, D., Thomas, L., Alewood, P. F. and Lewis, R. J. (2012), N- and c-terminal extensions of μ-conotoxins increase potency and selectivity for neuronal sodium channels . Biopolymers, 98: 161–165. doi: 10.1002/bip.22032
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Publication History
- Issue published online: 17 MAR 2012
- Article first published online: 10 FEB 2012
- Manuscript Accepted: 21 DEC 2011
- Manuscript Revised: 11 DEC 2011
- Manuscript Received: 31 OCT 2011
Funded by
- NHMRC Program. Grant Number: 351446
- Abstract
- Article
- References
- Cited By
Keywords:
- μ-conotoxin;
- radioligand binding;
- NMR spectroscopy;
- solution structure;
- sodium channel
Abstract
μ-Conotoxins are peptide blockers of voltage-gated sodium channels (sodium channels), inhibiting tetrodotoxin-sensitive neuronal (Nav1.2) and skeletal (Nav1.4) 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.