A humanized Gs-coupled DREADD for circuit and behavior modulation

Qi Zhang; Ruiqi Wang; Liang Zhang; Mengqi Li; Jianbang Lin; Xiaoyang Lu; Yixuan Tian; Yunping Lin; Taian Liu; Yefei Chen; Yuantao Li; Jun Cao; Qiang Wu; Jinhui Wang; Zhonghua Lu; Zexuan Hong

doi:10.3389/fncel.2025.1577117

A humanized Gs-coupled DREADD for circuit and behavior modulation

Front Cell Neurosci. 2025 Apr 9:19:1577117. doi: 10.3389/fncel.2025.1577117. eCollection 2025.

Authors

Qi Zhang^#¹, Ruiqi Wang^#², Liang Zhang^#³, Mengqi Li², Jianbang Lin^{2

4

5}, Xiaoyang Lu², Yixuan Tian², Yunping Lin^{2

4

5}, Taian Liu², Yefei Chen², Yuantao Li⁶, Jun Cao⁶, Qiang Wu^{3

7}, Jinhui Wang¹, Zhonghua Lu^{2

4

5

7}, Zexuan Hong⁶

Affiliations

¹ Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
² Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 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 Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, 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.

^# Contributed equally.

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: D1-MSNs; DREADD; Gs-signaling; modulation; neuronal activation; transgene modification.