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

TITLE=A humanized Gs-coupled DREADD for circuit and behavior modulation

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2025.1577117

DOI=10.3389/fncel.2025.1577117

ISSN=1662-5102

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.