A humanized Gs-coupled DREADD for circuit and behavior modulation
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 downstrea...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2025.1577117/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qi Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c5a4df6f17c34cff92eb4717fabe44da |
| institution | DOAJ |
| issn | 1662-5102 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj-art-c5a4df6f17c34cff92eb4717fabe44da2025-08-20T03:17:27ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022025-04-011910.3389/fncel.2025.15771171577117A humanized Gs-coupled DREADD for circuit and behavior modulationQi Zhang0Ruiqi Wang1Liang Zhang2Mengqi Li3Jianbang Lin4Jianbang Lin5Jianbang Lin6Xiaoyang Lu7Yixuan Tian8Yunping Lin9Yunping Lin10Yunping Lin11Taian Liu12Yefei Chen13Yuantao Li14Jun Cao15Qiang Wu16Qiang Wu17Jinhui Wang18Zhonghua Lu19Zhonghua Lu20Zhonghua Lu21Zhonghua Lu22Zexuan Hong23Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaDepartment of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen 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, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen 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, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaShenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaDepartment of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, ChinaState Key Laboratory of Biomedical Imaging Science and System, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, ChinaDepartment of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, ChinaResearch Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen 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, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Biomedical Imaging Science and System, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaDesigner 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.https://www.frontiersin.org/articles/10.3389/fncel.2025.1577117/fullDREADDneuronal activationmodulationtransgene modificationGs-signalingD1-MSNs |
| spellingShingle | 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 A humanized Gs-coupled DREADD for circuit and behavior modulation Frontiers in Cellular Neuroscience DREADD neuronal activation modulation transgene modification Gs-signaling D1-MSNs |
| title | A humanized Gs-coupled DREADD for circuit and behavior modulation |
| title_full | A humanized Gs-coupled DREADD for circuit and behavior modulation |
| title_fullStr | A humanized Gs-coupled DREADD for circuit and behavior modulation |
| title_full_unstemmed | A humanized Gs-coupled DREADD for circuit and behavior modulation |
| title_short | A humanized Gs-coupled DREADD for circuit and behavior modulation |
| title_sort | humanized gs coupled dreadd for circuit and behavior modulation |
| topic | DREADD neuronal activation modulation transgene modification Gs-signaling D1-MSNs |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2025.1577117/full |
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