Engineered Conotoxin Differentially Blocks and Discriminates Rat and Human α7 Nicotinic Acetylcholine Receptors

The alpha 7 nicotinic acetylcholine receptor (nAChR) is present in the central nervous system and plays an important role in cognitive function and memory. alpha-Conotoxin LvIB, identified from genomic DNA of Conus lividus, its three isomers and four globular isomer analogues were synthesized and screened at a wide range of nAChR subtypes. One of the analogues, amidated [Q1G, Delta R14]LvIB, was found to be a potent blocker of rat alpha 7 nAChRs. Importantly, it differentiates between alpha 7 nAChRs of human (IC50: 1570 nM) and rat (IC50: 97 nM). Substitutions between rat and human alpha 7 nAChRs at three key mutation sites revealed that no single mutant could completely change the activity profile of amidated [Q1G, Delta R14]LvIB. Rather, we found that the combined influence of Gln141, Asn184, and Lys186 determines the alpha 7 nAChR species specificity of this peptide. This engineered alpha 4/4 conotoxin has potential applications as a template for designing ligands to selectively block human alpha 7 nAChRs.

Automated summary

The study identified that amidated [Q1G, Delta R14]LvIB is a potent blocker of rat alpha 7 nAChRs and can differentiate between human and rat alpha 7 nAChRs. Substitutions at key mutation sites between rat and human alpha 7 nAChRs revealed that the combined influence of Gln141, Asn184, and Lys186 determines the alpha 7 nAChR species specificity of this peptide.