Frontiers in Cellular Neuroscience (Apr 2025)
A humanized Gs-coupled DREADD for circuit and behavior modulation
- Qi Zhang,
- Ruiqi Wang,
- Liang Zhang,
- Mengqi Li,
- Jianbang Lin,
- Jianbang Lin,
- Jianbang Lin,
- Xiaoyang Lu,
- Yixuan Tian,
- Yunping Lin,
- Yunping Lin,
- Yunping Lin,
- Taian Liu,
- Yefei Chen,
- Yuantao Li,
- Jun Cao,
- Qiang Wu,
- Qiang Wu,
- Jinhui Wang,
- Zhonghua Lu,
- Zhonghua Lu,
- Zhonghua Lu,
- Zhonghua Lu,
- Zexuan Hong
Affiliations
- Qi Zhang
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
- Ruiqi Wang
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Liang Zhang
- Department of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, China
- Mengqi Li
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Jianbang Lin
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Jianbang Lin
- Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Jianbang Lin
- University of Chinese Academy of Sciences, Beijing, China
- Xiaoyang Lu
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yixuan Tian
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yunping Lin
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yunping Lin
- Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yunping Lin
- University of Chinese Academy of Sciences, Beijing, China
- Taian Liu
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yefei Chen
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Yuantao Li
- Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China
- Jun Cao
- Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China
- Qiang Wu
- Department of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, China
- Qiang Wu
- State Key Laboratory of Biomedical Imaging Science and System, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China
- Jinhui Wang
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
- Zhonghua Lu
- Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Zhonghua Lu
- Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Zhonghua Lu
- University of Chinese Academy of Sciences, Beijing, China
- Zhonghua Lu
- State Key Laboratory of Biomedical Imaging Science and System, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China
- Zexuan Hong
- Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China
- DOI
- https://doi.org/10.3389/fncel.2025.1577117
- Journal volume & issue
-
Vol. 19
Abstract
Designer receptors exclusively activated by designer drugs (DREADDs) play important roles in neuroscience research and show great promise for future clinical interventions in neurological diseases. The Gs-coupled DREADD, rM3Ds, modulates excitability in neuron subsets that are sensitive to downstream effectors of Gs protein. However, given the non-human nature of the rM3Ds backbone, risks about potential immunogenicity and tolerability exist when considering clinical translation. Here, we report the development of a whole sequence-humanized Gs-coupled DREADD, hM3Ds. We found that hM3Ds has a comparable DREADD ligand response profile to rM3Ds. We then selectively expressed hM3Ds in D1 medium spiny neurons (D1-MSNs) and found that hM3Ds was able to activate the D1-MSNs-mediated basal ganglia direct pathway and alleviate Parkinsonian phenotypes in a Parkinson’s disease mouse model. In conclusion, this engineered humanized Gs-coupled DREADD is suitable as an effective, and likely safer, DREADD tool for both research and future clinical applications.
Keywords
