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

Nielsen, Katherine J. and Watson, Michael and Adams, David J. and Hammarstrom, Anna K. and Gage, Peter W. and Hill, Justine M. and Craik, David J. and Thomas, Linda and Adams, Denise and 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. ISSN 0021-9258

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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.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: © 2002 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher does not formally support archiving. Published version made not accessible.
Depositing User: Dr Michael Watson
Faculty / Department / School: Historic - Faculty of Sciences - Department of Biological and Physical Sciences
Date Deposited: 02 Dec 2007 03:06
Last Modified: 29 Oct 2013 05:03
Uncontrolled Keywords: assays; brain; conformations; electric potential; muscle; isomerization; neurology; nuclear magnetic resonance; sodium
Fields of Research (FOR2008): 06 Biological Sciences > 0601 Biochemistry and Cell Biology > 060105 Cell Neurochemistry
06 Biological Sciences > 0601 Biochemistry and Cell Biology > 060111 Signal Transduction
11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111506 Toxicology (incl.Clinical Toxicology)
Socio-Economic Objective (SEO2008): E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: doi: 10.1074/jbc.M201611200
URI: http://eprints.usq.edu.au/id/eprint/3243

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