Neuronally selective micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels

Schroeder, C.I, Ekberg, J, Nielsen, K.J, Adams, D, Loughnan, M L, Thomas, L, Adams, D J, Alewood, P F and Lewis, R J (2008) Neuronally selective micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels. Journal of Biological Chemistry, 283 31: 21621-21628. doi:10.1074/jbc.M802852200

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Author Schroeder, C.I
Ekberg, J
Nielsen, K.J
Adams, D
Loughnan, M L
Thomas, L
Adams, D J
Alewood, P F
Lewis, R J
Title Neuronally selective micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels
Formatted title
Neuronally Selective µ-Conotoxins from Conus striatus Utilize an alpha-Helical Motif to Target Mammalian Sodium Channels
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2008-08-01
Year available 2008
Sub-type Article (original research)
DOI 10.1074/jbc.M802852200
Open Access Status File (Publisher version)
Volume 283
Issue 31
Start page 21621
End page 21628
Total pages 8
Editor Tabor, H
Place of publication Bethesda, USA
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Language eng
Subject C1
110902 Cellular Nervous System
920111 Nervous System and Disorders
1115 Pharmacology and Pharmaceutical Sciences
0601 Biochemistry and Cell Biology
Abstract μ-Conotoxins are small peptide inhibitors of muscle and neuronal tetrodotoxin (TTX)-sensitive voltage-gated sodium channels (VGSCs). Here we report the isolation of μ-conotoxins SIIIA and SIIIB by 125I-TIIIA-guided fractionation of milked Conus striatus venom. SIIIA and SIIIB potently displaced 125I-TIIIA from native rat brain Nav1.2 (IC50 values 10 and 5 nM, respectively) and muscle Nav1.4 (IC50 values 60 and 3 nM, respectively) VGSCs, and both inhibited current through Xenopus oocyte-expressed Nav1.2 and Nav1.4. An alanine scan of SIIIA-(2–20), a pyroglutamate-truncated analogue with enhanced neuronal activity, revealed residues important for affinity and selectivity. Alanine replacement of the solvent-exposed Trp-12, Arg-14, His-16, Arg-18 resulted in large reductions in SIIIA-(2–20) affinity, with His-16 replacement affecting structure. In contrast, [D15A]SIIIA-(2–20) had significantly enhanced neuronal affinity (IC50 0.65 nM), while the double mutant [D15A/H16R]SIIIA-(2–20) showed greatest Nav1.2 versus 1.4 selectivity (136-fold). 1H NMR studies revealed that SIIIA adopted a single conformation in solution comprising a series of turns and anα-helical motif across residues 11–16 that is not found in larger μ-conotoxins. The structure of SIIIA provides a new structural template for the development of neuronally selective inhibitors of TTX-sensitive VGSCs based on the smaller μ-conotoxin pharmacophore.
Keyword Conus striatus
Conotoxin
Alpha-helical motif
Sodium channels
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Fri, 17 Apr 2009, 01:37:01 EST by Shirley Rey on behalf of Faculty of Science