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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1577117
A humanized Gs-coupled DREADD for circuit and behavior modulation
Provisionally accepted
Qi Zhang 1
Ruiqi Wang 2
Liang Zhang 3 Mengqi Li 2 Jianbang Lin 2,4,5 Xiaoyang Lu 2
Yixuan Tian 2 Yunping Lin 2,4,5 Taian Liu 2 Yefei Chen 2
Yuantao Li 6
Jun Cao 6
Qiang Wu 3* Jinhui Wang 1*
Zhonghua Lu 2,4,5,7
Zexuan Hong 8*- 1 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
- 2 Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Shenzhen, China
- 3 Department of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, China
- 4 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, China
- 5 University of Chinese Academy of Sciences, Beijing, Beijing, China
- 6 Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, Guangdong Province, China
- 7 State Key Laboratory of Biomedical Imaging Science and System, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China
- 8 Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
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: DREADD, neuronal activation, modulation, transgene modification, Gs signaling, D1-MSNs
Received: 15 Feb 2025; Accepted: 21 Mar 2025.
Copyright: © 2025 Zhang, Wang, Zhang, Li, Lin, Lu, Tian, Lin, Liu, Chen, Li, Cao, Wu, Wang, Lu and Hong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qiang Wu, Department of Anesthesiology, The Third People’s Hospital of Shenzhen, Shenzhen, China
Jinhui Wang, Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China
Zexuan Hong, Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
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