Characterization of a Novel Î±-Conotoxin TxIC from Conus textile that Potently Blocks rat Î±3Î²4 Nicotinic Acetylcholine Receptors
Sulan Luo , Dongting Zhangsun , Xiaopeng Zhu , Yong Wu , Yuanyan Hu , Sean Christensen , Peta J. Harvey , Muharrem Akcan , David J Craik , and J. Michael McIntosh, J. Med. Chem., Just Accepted Manuscript
Publication Date (Web): November 7, 2013
Copyright © 2013 American Chemical Society
The Î±3Î²4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an Î±-4/6-conotoxin (CTx) TxIC from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxIC was synthesized using solid phase methods and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxIC blocked rat Î±3Î²4 nAChRs with a 12.5 nM IC50, which places it amongst the most potent Î±3Î²4 nAChR antagonists. TxIC also blocked the closely related Î±6/Î±3Î²4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular Î±-CTx fold but with different surface charge distribution to other 4/6 family members. Î±-CTx TxIC is a novel tool with which to probe the structure and function of Î±3Î²4 nAChRs.