Conotoxins targeting voltage-gated sodium ion channels

芋螺毒素 钠通道 离子通道 化学 电压门控离子通道 二硫键 毒液 生物物理学 生物信息学 生物 生物化学 受体 有机化学
作者
Shengrong Pei,Nan Wang,Zaoli Mei,Dongting Zhangsun,David J. Craik,J. Michael McIntosh,Xiaopeng Zhu,Sulan Luo
出处
期刊:Pharmacological Reviews [American Society for Pharmacology & Experimental Therapeutics]
卷期号:: PHARMREV-000923 被引量:1
标识
DOI:10.1124/pharmrev.123.000923
摘要

Voltage-gated sodium (NaV) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases such as epilepsy, neuropathic pain, psychosis, autism and cardiac arrhythmia. Many venom peptides selectively act on NaV channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense, but which are also valuable pharmacological tools for the identification and/or treatment of human diseases. Typically, conotoxins contain two or three disulfide bonds and these internal cross-braces contribute to conotoxins having compact, well-defined structures and high stability. Of the conotoxins containing three disulfide bonds some selectively target mammalian NaV channels and can block, stimulate, or modulate these channels. Such conotoxins have great potential to serve as pharmacological tools for studying the functions and characteristics of NaV channels or as drug leads for neurological diseases related to NaV channels. Accordingly, discovering or designing conotoxins targeting NaV channels with high potency and selectivity is important. The amino acid sequences, disulfide bond connectivity, and three-dimensional structures are key factors that affect the biological activity of conotoxins, and targeted synthetic modifications of conotoxins can greatly improve their activity and selectivity. This review examines NaV channel-targeted conotoxins, focusing on their structures, activities and designed modifications, with a view towards expanding their applications. Significance Statement NaV channels are crucial in various neurological diseases. Some conotoxins selectively target NaV channels, causing either blockade or activation, thus enabling their use as pharmacological tools for studying the channels' characteristics and functions. Conotoxins also have promising potential to be developed as drug leads. The disulfide bonds in these peptides are important for stabilizing their structures, thus leading to enhanced specificity and potency. Together, conotoxins targeting NaV channels have both immediate research value and promising future application prospects.
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