A Novel α4/7-Conotoxin QuIA Selectively Inhibits α3β2 and α6/α3β4 Nicotinic Acetylcholine Receptor Subtypes with High Efficacy
2022
Liujun Wang | Xixi Wu | Xiaopeng Zhu | Dongting Zhangsun | Yong Wu | Sulan Luo
&alpha:6&beta:4 nAChR is expressed in the peripheral and central nervous systems and is associated with pain, addiction, and movement disorders. Natural &alpha:-conotoxins (&alpha:-CTxs) can effectively block different nAChR subtypes with higher efficacy and selectivity. However, the research on &alpha:6&beta:4 nAChR is relatively poor, partly because of the lack of available target-specific &alpha:-CTxs. In this study, we synthesized a novel &alpha:-4/7 conotoxin QuIA that was found from Conus quercinus. We investigated the efficacy of this peptide to different nAChR subtypes using a two-electrode voltage-clamp technique. Remarkably, we found &alpha:-QuIA inhibited the neuronal &alpha:3&beta:2 and &alpha:6/&alpha:3&beta:4 nAChR subtypes with significantly high affinity (IC50 was 55.7 nM and 90.68 nM, respectively), and did not block other nAChR subtypes even at a high concentration of 10 &mu:M. In contrast, most &alpha:-CTxs have been determined so far to effectively block the &alpha:6/&alpha:3&beta:4 nAChR subtype while also maintaining a similar higher efficacy against the closely related &alpha:6&beta:2&beta:3 and/or &alpha:3&beta:4 subtypes, which are different from QuIA. In conclusion, &alpha:-QuIA is a novel &alpha:4/7-CTx, which has the potential to develop as an effective neuropharmacology tool to detect the function of &alpha:6&beta:4 nAChR.
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