Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors.
Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors.
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DOI：
10.1038/nchem.1234
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发表时间：
2012-01-10
期刊：
影响因子：
21.8
通讯作者：
Trauner D
中科院分区：
文献类型：
--
作者：
Tochitsky I;Banghart MR;Mourot A;Yao JZ;Gaub B;Kramer RH;Trauner D
在合成化学、结构生物学、分子建模和分子克隆方面的进展使得能够对跨膜蛋白进行系统的功能操作。通过将基因操纵的蛋白质与光敏配体相结合，可以将天生的“盲”神经生物学受体转化为光受体，这使得它们能够以高时空精度进行光调节。在这里，我们提出了光化学控制的神经元烟碱乙酰胆碱受体（nAChRs）与光开关栓系激动剂和拮抗剂。使用基于结构的设计，我们产生了异聚体α3β4和α4β2 nAChR，它们可以被深紫光激活或抑制，但在黑暗中对乙酰胆碱反应正常。这些工程受体的产生应促进神经元nAChR的生理和病理功能的调查，并打开一个通用的途径，光敏五聚体配体门控离子通道。
Advances in synthetic chemistry, structural biology, molecular modelling and molecular cloning have enabled the systematic functional manipulation of transmembrane proteins. By combining genetically manipulated proteins with light-sensitive ligands, innately ‘blind’ neurobiological receptors can be converted into photoreceptors, which allows them to be photoregulated with high spatiotemporal precision. Here, we present the optochemical control of neuronal nicotinic acetylcholine receptors (nAChRs) with photoswitchable tethered agonists and antagonists. Using structure-based design, we produced heteromeric α3β4 and α4β2 nAChRs that can be activated or inhibited with deep-violet light, but respond normally to acetylcholine in the dark. The generation of these engineered receptors should facilitate investigation of the physiological and pathological functions of neuronal nAChRs and open a general pathway to photosensitizing pentameric ligand-gated ion channels.