A novel α4/7-conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors

摘要: 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, cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes determined by 2-electrode voltage-clamp electrophysiology, its 3-dimensional (3D) structure NMR spectroscopy. α-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using subunits expressed in oocytes, we found highest affinity of α-CTxLvIA for α3β2 nAChRs (IC50 8.7 nM), where blockade reversible within 2 min. IC50 values were >100 nM α6/α3β2β3, α6/α3β4, α3β4 nAChRs, ≥3 μM all other tested. vs. α6β2 subtype selectivity confirmed human-subunit much greater preference (300-fold) over nAChRs. reported show high human adopts two similarly populated conformations water: one (assumed be bioactive) highly structured, whereas mostly random coil nature. Selectivity differences potent, but less selective, antagonist PeIA probably reside three residues, which differ loop 2, given their otherwise similar 3D structures. α4/7-CTx new, selective antagonist, will enable detailed studies structure, function, physiological roles.—Luo, S., Zhangsun, D., Schroeder, C. I., Zhu, X., Hu, Y., Wu, Weltzin, M. M., Eberhard, Kaas, Q., Craik, D. J., McIntosh, J. Whiteaker, P. α4/7-conotoxin lividus that selectively blocks α6/α3β2β3 receptors.