<br>Bis-CNB-GABA（一种具有低受体干扰和化学双光子解笼特性的光激活神经递质）的合成和生物学评价,Journal of the American Chemical Society

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Bis-CNB-GABA（一种具有低受体干扰和化学双光子解笼特性的光激活神经递质）的合成和生物学评价
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2014-01-27 , DOI: 10.1021/ja411082f
Diana D Shi ₁ , Federico F Trigo , Martin F Semmelhack , Samuel S-H Wang

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可光激活的“笼式”神经递质允许以高空间和时间精度对神经组织进行光学控制。然而，主要脊椎动物抑制性神经递质γ-氨基丁酸（GABA）的笼式版本的开发受到笼式GABA与GABA受体相互作用的倾向的限制。我们在此描述了一种实用的双笼GABA类似物的合成和应用，称为双-α-羧基-2-硝基苄基-GABA（双-CNB-GABA）。双 CNB-GABA 的解禁会在小脑分子层中间神经元中引起向内 GABA 电流，上升时间为 2 毫秒，与闪光持续时间相当。响应幅度取决于闪光强度的平方，正如化学双光子解笼效应所预期的那样。重要的是，在解笼之前，bis-CNB-GABA 在 GABAA 受体上不活跃，不会引起电压钳位神经元中的保持电流变化，并且使用自发 GABA 突触电流测量显示 IC50 至少为 2.5 mM。 Bis-CNB-GABA 在溶液中稳定，光照下半衰期估计为 98 天。我们预计 bis-CNB-GABA 将被证明是脑回路高分辨率化学控制的有效工具。

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Synthesis and Biological Evaluation of Bis-CNB-GABA, a Photoactivatable Neurotransmitter with Low Receptor Interference and Chemical Two-Photon Uncaging Properties

Photoactivatable “caged” neurotransmitters allow optical control of neural tissue with high spatial and temporal precision. However, the development of caged versions of the chief vertebrate inhibitory neurotransmitter, γ-amino butyric acid (GABA), has been limited by the propensity of caged GABAs to interact with GABA receptors. We describe herein the synthesis and application of a practically useful doubly caged GABA analog, termed bis-α-carboxy-2-nitrobenzyl-GABA (bis-CNB-GABA). Uncaging of bis-CNB-GABA evokes inward GABAergic currents in cerebellar molecular layer interneurons with rise times of 2 ms, comparable to flash duration. Response amplitudes depend on the square of flash intensity, as expected for a chemical two-photon uncaging effect. Importantly, prior to uncaging, bis-CNB-GABA is inactive at the GABAA receptor, evoking no changes in holding current in voltage-clamped neurons and showing an IC50 of at least 2.5 mM as measured using spontaneous GABAergic synaptic currents. Bis-CNB-GABA is stable in solution, with an estimated half-life of 98 days in the light. We expect that bis-CNB-GABA will prove to be an effective tool for high-resolution chemical control of brain circuits.

更新日期：2014-01-27

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