Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

Hopping, Gene, Wang, C-I Anderson, Hogg, Ron C., Nevin, Simon T., Lewis, Richard J., Adams, David J. and Alewood, Paul F. (2014) Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors. Biochemical Pharmacology, 91 4: 534-542. doi:10.1016/j.bcp.2014.07.025

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Author Hopping, Gene
Wang, C-I Anderson
Hogg, Ron C.
Nevin, Simon T.
Lewis, Richard J.
Adams, David J.
Alewood, Paul F.
Title Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
1873-2968
Publication date 2014
Sub-type Article (original research)
DOI 10.1016/j.bcp.2014.07.025
Open Access Status File (Author Post-print)
Volume 91
Issue 4
Start page 534
End page 542
Total pages 9
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2015
Language eng
Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are a diverse class of ligand-gated ion channels involved in neurological conditions such as neuropathic pain and Alzheimer's disease. α-Conotoxin [A10L]PnIA is a potent and selective antagonist of the mammalian α7 nAChR with a key binding interaction at position 10. We now describe a molecular analysis of the receptor-ligand interactions that determine the role of position 10 in determining potency and selectivity for the α7 and α3β2 nAChR subtypes. Using electrophysiological and radioligand binding methods on a suite of [A10L]PnIA analogs we observed that hydrophobic residues in position 10 maintained potency at both subtypes whereas charged or polar residues abolished α7 binding. Molecular docking revealed dominant hydrophobic interactions with several α7 and α3β2 receptor residues via a hydrophobic funnel. Incorporation of norleucine (Nle) caused the largest (8-fold) increase in affinity for the α7 subtype (Ki = 44 nM) though selectivity reverted to α3β2 (IC50 = 0.7 nM). It appears that the placement of a single methyl group determines selectivity between α7 and α3β2 nAChRs via different molecular determinants.
Keyword Alpha-conotoxin
Nicotinic acetylcholine receptors
Structure-function relationship
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 2015 Collection
Institute for Molecular Bioscience - Publications
 
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