2mdq

Publication Abstract from PubMed

This study was performed to discover and characterize the first potent alpha3beta2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel alpha4/7-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 alpha3beta2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were >100 nM at alpha6/alpha3beta2beta3, alpha6/alpha3beta4, and alpha3beta4 nAChRs, and >/=3 muM at all other subtypes tested. alpha3beta2 vs. alpha6beta2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for alpha3beta2 over alpha6beta2 nAChRs. This is the first alpha-CTx reported to show high selectivity for human alpha3beta2 vs. alpha6beta2 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, alpha3beta2 nAChR antagonist alpha-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. alpha4/7-CTx LvIA is a new, potent, selective alpha3beta2 nAChR antagonist, which will enable detailed studies of alpha3beta2 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 alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3beta2 vs. alpha6/alpha3beta2beta3 nicotinic acetylcholine receptors.

A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3beta2 vs. alpha6/alpha3beta2beta3 nicotinic acetylcholine receptors.,Luo S, Zhangsun D, Schroeder CI, Zhu X, Hu Y, Wu Y, Weltzin MM, Eberhard S, Kaas Q, Craik DJ, McIntosh JM, Whiteaker P FASEB J. 2014 Jan 7. PMID:24398291^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.