Solution structure of μ-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels

Article


Nielsen, Katherine J., Watson, Michael, Adams, David J., Hammarstrom, Anna K., Gage, Peter W., Hill, Justine M., Craik, David J., Thomas, Linda, Adams, Denise, Alewood, Paul F. and Lewis, Richard J.. 2002. "Solution structure of μ-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels ." Journal of Biological Chemistry. 277 (30), pp. 27247-27255. https://doi.org/10.1074/jbc.M201611200
Article Title

Solution structure of μ-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels

ERA Journal ID2230
Article CategoryArticle
AuthorsNielsen, Katherine J. (Author), Watson, Michael (Author), Adams, David J. (Author), Hammarstrom, Anna K. (Author), Gage, Peter W. (Author), Hill, Justine M. (Author), Craik, David J. (Author), Thomas, Linda (Author), Adams, Denise (Author), Alewood, Paul F. (Author) and Lewis, Richard J. (Author)
Journal TitleJournal of Biological Chemistry
Journal Citation277 (30), pp. 27247-27255
Number of Pages9
Year2002
Place of PublicationBethesda, MD. United States
ISSN0021-9258
1083-351X
Digital Object Identifier (DOI)https://doi.org/10.1074/jbc.M201611200
Web Address (URL)http://www.jbc.org/cgi/reprint/277/30/27247
Abstract

μ-Conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of μ-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current in sensory ganglion neurons. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA-(2-22), and μ-conotoxin GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, and GIIIA had low affinity for neuronal VSSCs. 1H NMR studies found that PIIIA adopts two conformations in solution due to cis/trans isomerization at hydroxyproline 8. The major trans conformation results in a three-dimensional structure that is significantly different from the previously identified conformation of μ-conotoxins GIIIA and GIIIB that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective μ-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by μ-conotoxins.

Keywordsassays; brain; conformations; electric potential; muscle; isomerization; neurology; nuclear magnetic resonance; sodium
ANZSRC Field of Research 2020310104. Cell neurochemistry
310111. Signal transduction
321407. Toxicology (incl. clinical toxicology)
Public Notes

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher does not formally support archiving. Published version made not accessible.

Byline AffiliationsUniversity of Queensland
Department of Biological and Physical Sciences
Australian National University
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