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2399-3642812025Nov28Communications biologyCommun BiolNeuronal activity-induced GLUT3 plasma translocation supports energy demands for memory acquisition.17161716171610.1038/s42003-025-09119-zGlucose transporter 3 (GLUT3) is crucial for glucose uptake in neurons and rapidly translocates to the plasma membrane in response to neural activity. However, the precise molecular mechanisms and physiological roles of this translocation remain elusive, hindering our understanding of how glucose metabolism supports brain function. This study found that PKCε phosphorylates Thr232 and Ser246 of GLUT3 upon neuronal activation, enhancing its binding to KLC1 and promoting GLUT3 plasma membrane insertion. To investigate the function of GLUT3 plasma translocation, we developed a peptide, TAT-GLUT3(2D), which disrupts GLUT3-KLC1 binding and blocks activity-dependent translocation of GLUT3. By utilizing TAT-GLUT3(2D), we showed that blockage of activity-induced GLUT3 neuronal surface translocation leads to decreased glucose uptake and ATP production, impairing memory acquisition without affecting memory consolidation or retrieval in mice. Our results suggest that PKCε-mediated phosphorylation of GLUT3 is a key regulator of neuronal activity-induced GLUT3 plasma membrane insertion and memory acquisition, advancing our understanding of the energy supply needed for memory acquisition.© 2025. The Author(s).WeiXin-YueXY0009-0003-1192-1374Department of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.ZouZe-MingZMDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.YaoZhong-XiaoZXDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.TengShuai-WenSWDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China.WeiXin-YuXYDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.TangWen-JieWJDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.ChenXiao-LinXLDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.HeYun-ZhangYZDepartment of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.ChenZhe-YuZY0000-0002-7092-8723Department of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China. zheyuchen@sdu.edu.cn.Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China. zheyuchen@sdu.edu.cn.State Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, China. zheyuchen@sdu.edu.cn.eng32471068National Natural Science Foundation of China (National Science Foundation of China)Journal Article20251128
EnglandCommun Biol1017191792399-36420Glucose Transporter Type 3IY9XDZ35W2GlucoseEC 2.7.11.13Protein Kinase C-epsilon0Slc2a3 protein, mouseIMAnimalsGlucose Transporter Type 3metabolismgeneticsNeuronsmetabolismMicePhosphorylationCell MembranemetabolismProtein TransportEnergy MetabolismMemoryphysiologyGlucosemetabolismMaleProtein Kinase C-epsilonmetabolismMice, Inbred C57BLHumansCompeting interests: The authors declare no competing interests.20252212025101720251129629202511292212025112903020251128epublish41315759PMC1266346610.1038/s42003-025-09119-z10.1038/s42003-025-09119-zMagistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron86, 883–901 (2015). 10.1016/j.neuron.2015.03.03525996133Diaz-Garcia, C. M. et al. Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab.26, 361–374 (2017). 10.1016/j.cmet.2017.06.021PMC555989628768175Belanger, M., Allaman, I. & Magistretti, P. J. 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