Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABA(B) receptor-coupled N-type calcium channels

Daly, Norelle L., Callaghan, Brid, Clark, Richard J., Nevin, Simon T., Adams, David J. and Craik, David J. (2011) Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABA(B) receptor-coupled N-type calcium channels. Journal of Biological Chemistry, 286 12: 10233-10237. doi:10.1074/jbc.M110.196170

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Author Daly, Norelle L.
Callaghan, Brid
Clark, Richard J.
Nevin, Simon T.
Adams, David J.
Craik, David J.
Title Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABA(B) receptor-coupled N-type calcium channels
Formatted title
Structure and activity of α-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABAB receptor-coupled N-type calcium channels
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
1067-8816
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1074/jbc.M110.196170
Open Access Status File (Publisher version)
Volume 286
Issue 12
Start page 10233
End page 10237
Total pages 5
Place of publication Bethesda, MD, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2012
Language eng
Formatted abstract
α-Conotoxins are peptides from cone snails that target the nicotinic acetylcholine receptor (nAChR). RgIA and Vc1.1 have analgesic activity in animal pain models. Both peptides target the α9α10 nAChR and inhibit N-type calcium channels via GABAB receptor activation, but the mechanism of action of analgesic activity is unknown. PeIA has previously been shown to inhibit the α9α10 and α3β2 nAChRs. In this study, we have determined the structure of PeIA and shown that it is also a potent inhibitor of N-type calcium channels via GABAB receptor activation. The characteristic α-conotoxin fold is present in PeIA, but it has a different distribution of surface-exposed hydrophobic and charged residues compared with Vc1.1. Thus, the surface residue distribution, rather than the overall fold, appears to be responsible for the 50-fold increase in selectivity at the α3β2 nAChR by PeIA relative to Vc1.1. In contrast to their difference in potency at the nAChR, the equipotent activity of PeIA and Vc1.1 at the GABAB receptor suggests that the GABAB receptor is more tolerant to changes in surface residues than is the nAChR. The conserved Asp-Pro-Arg motif of Vc1.1 and RgIA, which is crucial for potency at the α9α10 nAChR, is not required for activity at GABAB receptor/N-type calcium channels because PeIA has a His-Pro-Ala motif in the equivalent position. This study shows that different structure-activity relationships are associated with the targeting of the GABAB receptor versus nAChRs. Furthermore, there is probably a much more diverse range of conotoxins that target the GABAB receptor than currently realized.
Keyword Rat sensory neurons
Neuropathic pain
alpha-9-alpha-10
Vc1.1
Inhibition
RgIA
Antagonists
Modulation
Discovery
Peptides
α9α10
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 16 times in Scopus Article | Citations
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Created: Tue, 20 Sep 2011, 12:24:12 EST by Dr Richard Clark on behalf of Institute for Molecular Bioscience