A high-performance fluorescent sensor spatiotemporally reveals cell-type specific regulation of intracellular adenosine in vivo

Qingpeng Wei, Zexiao Bai, Lei Wang, Jing Wang, Yipan Wang, Yufei Hu, Shiyi Ding, Zhixiong Ma, Chun Li, Yumo Li, Yizhou Zhuo, Wenzhe Li, Fei Deng, Bingjie Liu, Pengcheng Zhou, Yulong Li (), Zhaofa Wu () and Jing Wang ()
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Qingpeng Wei: Peking University
Zexiao Bai: Chinese Academy of Sciences
Lei Wang: Peking University
Jing Wang: Chinese Academy of Sciences
Yipan Wang: Peking University
Yufei Hu: Peking University
Shiyi Ding: University of Chinese Academy of Sciences
Zhixiong Ma: Chinese Academy of Sciences
Chun Li: Chinese Academy of Sciences
Yumo Li: Chinese Academy of Sciences
Yizhou Zhuo: Peking University
Wenzhe Li: Peking University
Fei Deng: Peking University
Bingjie Liu: Peking University
Pengcheng Zhou: Chinese Academy of Sciences
Yulong Li: Peking University
Zhaofa Wu: Chinese Academy of Sciences
Jing Wang: Peking University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Adenosine (Ado), a nucleoside bridging intracellular metabolism with intercellular communication, plays an essential role in regulating processes such as sleep and seizure. While the functions of extracellular Ado (“eAdo”) are well documented, our knowledge about the distribution and regulatory functions of intracellular Ado (“iAdo”) is limited by a lack of methods for detecting iAdo in vivo. Here, we develop HypnoS, a genetically encoded fluorescent sensor for iAdo characterized by its high sensitivity, specificity, spatiotemporal resolution, and rapid response (sub-seconds). HypnoS enables real-time visualization of iAdo dynamics in live cultures, acute brain slices, flies, and freely moving mice. Using HypnoS for dual-color mesoscopic imaging in mice, we show that seizure-induced iAdo waves propagated across the cortex, following calcium signals. Additionally, two-photon imaging reveals that iAdo decays more rapidly in astrocytes than in neurons during seizures. Moreover, by recording iAdo dynamics in the basal forebrain during the sleep-wake cycle, we observe that iAdo signals are present during wakefulness and rapid eye movement (REM) sleep, regulated by equilibrative nucleoside transporters (ENT1/2). Thus, HypnoS is a versatile and powerful tool for investigating the biological functions of iAdo across a range of physiological and pathological states.

Date: 2025
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DOI: 10.1038/s41467-025-59530-7

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