A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3 beta2 vs. alpha6/alpha3 beta2 beta3 nicotinic acetylcholine receptors

Luo, Sulan, Zhangsun, Dongting, Schroeder, Christina I., Zhu, Xiaopeng, Hu, Yuanyan, Wu, Yong, Weltzin, Maegan M., Eberhard, Spencer, Kaas, Quentin, Craik, David J., McIntosh, J. Michael and Whiteaker, Paul (2014) A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3 beta2 vs. alpha6/alpha3 beta2 beta3 nicotinic acetylcholine receptors. FASEB Journal, Early Edition 4: 1-12. doi:10.1096/fj.13-244103

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Author Luo, Sulan
Zhangsun, Dongting
Schroeder, Christina I.
Zhu, Xiaopeng
Hu, Yuanyan
Wu, Yong
Weltzin, Maegan M.
Eberhard, Spencer
Kaas, Quentin
Craik, David J.
McIntosh, J. Michael
Whiteaker, Paul
Title A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3 beta2 vs. alpha6/alpha3 beta2 beta3 nicotinic acetylcholine receptors
Formatted title
A novel α4/7-conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors
Journal name FASEB Journal   Check publisher's open access policy
ISSN 0892-6638
1530-6860
Publication date 2014-01-07
Year available 2014
Sub-type Article (original research)
DOI 10.1096/fj.13-244103
Open Access Status Not yet assessed
Volume Early Edition
Issue 4
Start page 1
End page 12
Total pages 12
Place of publication Bethesda, MD, United States
Publisher Federation of American Societies for Experimental Biology
Language eng
Abstract This study was performed to discover and characterize the first potent alpha 3 beta 2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel alpha 4/7-conotoxin, alpha-CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes was determined by 2-electrode voltage-clamp electrophysiology, and its 3-dimensional (3D) structure was determined by NMR spectroscopy. alpha-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of alpha-CTxLvIA was for alpha 3 beta 2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were > 100 nM at alpha 6/alpha 3 beta 2 beta 3, alpha 6/alpha 3 beta 4, and alpha 3 beta 4 nAChRs, and >= 3 mu M at all other subtypes tested. alpha 3 beta 2 vs. alpha 6 beta 2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for alpha 3 beta 2 over alpha 6 beta 2 nAChRs. This is the first alpha-CTx reported to show high selectivity for human alpha 3 beta 2 vs. alpha 6 beta 2 nAChRs. alpha-CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, alpha 3 beta 2 nAChR antagonist alpha-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. alpha 4/7-CTx LvIA is a new, potent, selective alpha 3 beta 2 nAChR antagonist, which will enable detailed studies of alpha 3 beta 2 nAChR structure, function, and physiological roles.-Luo, S., Zhangsun, D., Schroeder, C. I., Zhu, X., Hu, Y., Wu, Y., Weltzin, M. M., Eberhard, S., Kaas, Q., Craik, D. J., McIntosh, J. M., Whiteaker, P. A novel alpha 4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha 3 beta 2 vs. alpha 6/alpha 3 beta 2 beta 3 nicotinic acetylcholine receptors.
Formatted abstract
This study was performed to discover and characterize the first potent α3β2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel α4/7-conotoxin, α-CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes was determined by 2-electrode voltage-clamp electrophysiology, and its 3-dimensional (3D) structure was determined by NMR spectroscopy. α-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of α-CTxLvIA was for α3β2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were >100 nM at α6/α3β2β3, α6/α3β4, and α3β4 nAChRs, and ≥3 μM at all other subtypes tested. α3β2 vs. α6β2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for α3β2 over α6β2 nAChRs. This is the first α-CTx reported to show high selectivity for human α3β2 vs. α6β2 nAChRs. α-CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, α3β2 nAChR antagonist α-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. α4/7-CTx LvIA is a new, potent, selective α3β2 nAChR antagonist, which will enable detailed studies of α3β2 nAChR structure, function, and physiological roles.
Keyword Ligand-gated ion channel receptor
Cholinergic
Nuclear magnetic resonance spectroscopy
Molecular modeling
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 81160503
2012AA021706
2011DFR31210
IRT1123
DA012242
1093115
Institutional Status UQ
Additional Notes Published online before print January 7, 2014.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 16 Jan 2014, 01:10:00 EST by Susan Allen on behalf of Institute for Molecular Bioscience