爪蟾
烟碱激动剂
化学
乙酰胆碱受体
芋螺毒素
离子通道
电压钳
配体(生物化学)
受体
烟碱乙酰胆碱受体
配体门控离子通道
肽
药理学
生物化学
荧光
生物物理学
生物
膜电位
基因
物理
量子力学
作者
Yishuai Yang,Yulong Tan,Dongting Zhangsun,Xiaopeng Zhu,Sulan Luo
标识
DOI:10.1021/acschemneuro.1c00392
摘要
Nicotinic acetylcholine receptors (nAChRs) are essential pentameric ligand-gated ion channels that are distributed throughout the central and peripheral nervous systems and non-neuronal tissues in mammalian species that play critical roles in a variety of neural and mental activities. The α3β2 nAChR subtype participates in pain, addiction to nicotine, and other neurophysiological and pathological activities. Owing to the lack of highly selective pharmacological tools targeting α3β2, related research on its tissue distribution and function has been hindered. α-Conotoxin (α-CTx) LtIA, discovered from Conus literatus in our lab, potently and selectively blocks α3β2 nAChR, providing an important molecular probe to study the α3β2 nAChR structure and function. We used the fluorescent molecule 5-carboxytetramethylrhodamine succinimidyl ester, which can react with the N-terminus of LtIA, to obtain a novel fluorescent analogue of LtIA (LtIA-F). The potency and selectivity of LtIA-F were tested using a two-electrode voltage clamp recording on various nAChRs expressed in Xenopus laevis oocytes. LtIA-F potently inhibited ACh-evoked currents at the α3β2 nAChR, with an IC50 value of 90.66 nM, displaying a ∼4-fold decrease in potency compared with native LtIA without a change in selectivity. The serum stability results indicated that LtIA-F exhibited stability similar to that of native LtIA. This study on an α-CTx LtIA fluorescent analogue provides a wealth of pharmacological tools to explore the structure-function relationship, distribution, and ligand binding domain of the α3β2 nAChR subtype.
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