Photoactivatable Dopamine and Sulpiride to Explore the Function of Dopaminergic Neurons and Circuits.,ACS Chemical Neuroscience

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Photoactivatable Dopamine and Sulpiride to Explore the Function of Dopaminergic Neurons and Circuits.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-03-04 , DOI: 10.1021/acschemneuro.9b00675
Naeem Asad ₁ , Duncan E McLain _{1,

2} , Alec F Condon ₃ , Sangram Gore ₁ , Shahienaz E Hampton ₁ , Sauparnika Vijay ₁ , John T Williams ₃ , Timothy M Dore _{1,

2}

Affiliation

Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of the neurotransmitter dopamine and tight temporal control over the release of dopamine receptor antagonists. The 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group was conjugated to dopamine and the dopamine receptor antagonist sulpiride to generate "caged" versions of these neuromodulators (CyHQ-O-DA and CyHQ-sulpiride, respectively) that could release their payloads with 365 or 405 nm light or through 2-photon excitation (2PE) at 740 nm. These compounds are stable under physiological conditions in the dark, yet photolyze rapidly and cleanly to yield dopamine or sulpiride and the caging remnant CyHQ-OH. CyHQ-O-DA mediated the light activation of dopamine-1 (D1) receptors on the breast cancer cell line MDA-MB-231 in culture. In mouse brain slice from the substantia nigra pars compacta, localized flash photolysis of CyHQ-O-DA accurately mimicked the natural presynaptic release of dopamine and activation of dopamine-2 (D2) receptors, causing a robust, concentration-dependent, and repeatable G protein-coupled inwardly rectifying potassium channel-mediated outward current in whole-cell voltage clamp recordings that was amplified by cocaine and blocked by sulpiride. Photolysis of CyHQ-sulpiride rapidly blocked synaptic activity, enabling measurement of the unbinding rates of dopamine and quinpirole, a D2 receptor agonist. These tools will enable more detailed study of dopamine receptors, their interactions with other GPCRs, and the physiology of dopamine signaling in the brain.

中文翻译：

光敏性多巴胺和舒必利，探索多巴胺能神经元和电路的功能。

多巴胺受体激活和失活的动力学分析以及对多巴胺依赖性信号传导的研究需要精确模拟神经递质多巴胺的突触前释放，并严格控制多巴胺受体拮抗剂的释放。将8-氰基-7-羟基喹啉基（CyHQ）可光除去的保护基与多巴胺和多巴胺受体拮抗剂舒必利结合，以生成这些神经调节剂的“笼状”版本（分别为CyHQ-O-DA和CyHQ-舒必利）。 365或405 nm的光或通过740 nm的2光子激发（2PE）产生的有效载荷。这些化合物在黑暗中在生理条件下稳定，但可以快速清洁地光解，产生多巴胺或舒必利以及笼中残留的CyHQ-OH。CyHQ-O-DA介导培养的乳腺癌细胞系MDA-MB-231上的多巴胺-1（D1）受体的光活化。在来自黑质致密部的小鼠脑切片中，CyHQ-O-DA的局部快速光解可准确模拟多巴胺的天然突触前释放和多巴胺2（D2）受体的激活，从而产生强大的，浓度依赖性和可重复的G在全细胞电压钳记录中，蛋白偶联的内向整流钾通道介导的外向电流被可卡因放大并被舒必利阻断。CyHQ-sulpiride的光解作用迅速阻断了突触活性，从而能够测量D2受体激动剂多巴胺和喹吡罗的未结合率。这些工具将有助于更详细地研究多巴胺受体，它们与其他GPCR的相互作用，

更新日期：2020-03-05

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