Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor

Author:

Wu Zhaofa123ORCID,Cui Yuting45,Wang Huan12ORCID,Wu Hao6,Wan Yi123,Li Bohan123,Wang Lei127,Pan Sunlei123,Peng Wanling8ORCID,Dong Ao123ORCID,Yuan Zhengwei46,Jing Miao5ORCID,Xu Min8ORCID,Luo Minmin4591011ORCID,Li Yulong1231213ORCID

Affiliation:

1. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China

2. IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China

3. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China

4. National Institute of Biological Sciences, Beijing 102206, China

5. Chinese Institute for Brain Research, Beijing 102206, China

6. School of Life Sciences, Tsinghua University, Beijing 100084, China

7. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Peking University, Beijing 100871, China

8. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China

9. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China

10. Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing 100005, China

11. New Cornerstone Science Institute at Chinese Institute for Brain Research, Beijing 102206, China

12. Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China

13. National Biomedical Imaging Center, Peking University, Beijing 100871, China

Abstract

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, the exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based Ado fluorescent sensor (GRAB Ado ), we discovered that the neuronal activity–induced extracellular Ado elevation is due to direct Ado release from somatodendritic compartments of neurons, rather than from the axonal terminals, in the hippocampus. Pharmacological and genetic manipulations reveal that the Ado release depends on equilibrative nucleoside transporters but not the conventional vesicular release mechanisms. Compared with the fast-vesicular glutamate release, the Ado release is slow (~40 s) and requires calcium influx through L-type calcium channels. Thus, this study reveals an activity-dependent second-to-minute local Ado release from the somatodendritic compartments of neurons, potentially serving modulatory functions as a retrograde signal.

Funder

Beijing Municipal Science and Technology Commission

National Natural Science Foundation of China

The "Strategic Priority Research Program" of the Chinese Academy of Sciences

MOST | National Key Research and Development Program of China

STI2030-Major Projects

The Research Unit of Medical Neurobiology at Chinese Academy of Medical Sciences

New Cornerstone Investigator Program

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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