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A Novel α4/7-Conotoxin Lvia From Conus Lividus That Selectively Blocks α3β2 Vs. α6/α3β2β3 Nicotinic Acetylcholine Receptors
Authors
David J. Craik
Spencer Eberhard
+10 more
Yuanyan Hu
Quentin Kaas
Sulan Luo
J. Michael McIntosh
Christina I. Schroeder
Maegan M. Weltzin
Paul Whiteaker
Yong Wu
Dongting Zhangsun
Xiaopeng Zhu
Publication date
1 January 2014
Publisher
Barrow - St. Joseph\u27s Scholarly Commons
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-terminallyamidated 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 \u3e100 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. © FASEB
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Last time updated on 11/05/2020