TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel.
TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel.
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TRPswitch-A Step-Function Chemo-Optogenetic Ligand for the Vertebrate TRPA1 Channel.
DOI：
10.1021/jacs.0c06811
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发表时间：
2020-10-14
影响因子：
15
通讯作者：
Peterson RT
中科院分区：
文献类型：
--
作者：
Lam PY;Thawani AR;Balderas E;White AJP;Chaudhuri D;Fuchter MJ;Peterson RT
化学光遗传学已经为细胞活动的光学控制提供了强大的工具，但目前的工具受到各种限制，包括低单位电导，需要修改靶通道，或者无法同时控制开关开关。利用斑马鱼基于行为的筛选策略，我们发现了“TRPSwitch”，这是一种可光开关的非亲电配体支架，用于瞬时受体潜在锚蛋白1(TRPA1)通道。TRPA1具有高的单位通道电导，使其成为化学光遗传工具开发的理想靶点。阐明了TRPSwitch活性的关键分子决定因素，并允许用下一代偶氮杂芳烃取代TRPSwitch偶氮苯。TRPSwitch化合物能够分别用紫光和绿光可逆、可重复和近乎定量的光诱导脊椎动物TRPA1通道的激活和失活。TRPSwitch化合物在外源表达斑马鱼Trpa1b的斑马鱼幼体心脏中的应用被证明，其中心跳可以通过TRPSwitch和光来控制。因此，TRPA1/TRPSwitch代表了一种新的阶跃功能化学光遗传系统，具有高电导、高效率、针对未经修饰的脊椎动物通道的活性以及双向光开关的能力的独特组合。这种化学光遗传系统将特别适用于需要大的去极化电流或需要持续的通道激活的系统。
Chemo-optogenetics has produced powerful tools for optical control of cell activity, but current tools suffer from a variety of limitations including low unitary conductance, the need to modify the target channel, or the inability to control both on and off switching. Using a zebrafish behavior-based screening strategy, we discovered “TRPswitch”, a photoswitchable non-electrophilic ligand scaffold for the transient receptor potential ankyrin 1 (TRPA1) channel. TRPA1 exhibits high unitary channel conductance, making it an ideal target for chemo-optogenetic tool development. Key molecular determinants for the activity of TRPswitch were elucidated and allowed for replacement of the TRPswitch azobenzene with a next-generation azoheteroarene. The TRPswitch compounds enable reversible, repeatable, and nearly quantitative light-induced activation and deactivation of the vertebrate TRPA1 channel with violet and green light, respectively. The utility of TRPswitch compounds was demonstrated in larval zebrafish hearts exogenously expressing zebrafish Trpa1b, where heartbeat could be controlled using TRPswitch and light. Therefore, TRPA1/TRPswitch represents a novel step-function chemo-optogenetic system with a unique combination of high conductance, high efficiency, activity against an unmodified vertebrate channel, and capacity for bidirectional optical switching. This chemo-optogenetic system will be particularly applicable in systems where a large depolarization current is needed or sustained channel activation is desirable.
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