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Angew. Chem.-Int. Edit., Jul 30 2025, | https://doi.org/10.1002/anie.202511160 Unraveling the Mode of Action of a Neuron-Specific Fluorescent Probe, NeuO: Intracellular Phosphorylation Through PAK6 Kinase

Beomsue Kim ^{1 *}, Dongwan Ko ¹, Sang-Bum Kim ², Songhui Kim ¹, Minji Kim ¹, Na-Kyeong Hong ³, Sun You Park ², Wonju Kim ¹, Byoung-Cheol Lee ⁴, Yunbeom Lee ⁵, Taebo Sim ⁶, Young-Tae Chang^{3 *}

¹Neural Circuits Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
²New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu, 41061, Republic of Korea.
³Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
⁴Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
⁵Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
⁶Department of Biomedical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

^*Corresponding authors: correspondence to Beomsue Kim or Young-Tae Chang

Abstract

NeuO is an intriguing molecular probe capable of selectively labeling live neurons within a heterogeneous population of brain cells. The precise mechanism responsible for this neuronal labeling has remained a longstanding enigma. We investigated four potential mechanisms underlying NeuO's fluorescence, including its interaction with neuronal proteins, transportation into neurons, export from glial cells, and structural alterations within neurons. Our study found that NeuO undergoes structural changes via phosphorylation by the PAK6 kinase, resulting in high fluorescence in neurons, likely due to fluorogenic activation and intracellular retention within neurons. This discovery improves our understanding of the molecular mechanism of NeuO in neurons and facilitates the development of new chemical compounds that can be selectively modified by kinases in living cells.

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