Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects

The TRPC1/5 heteromer exhibits electrophysiological and ligand-binding properties distinct from TRPC5 homomers, enabling tissue-specific cellular regulation. Here we present the cryo-EM structure of the TRPC1/5 heterotetramer at 2.8 Å resolution, revealing an asymmetric assembly of three TRPC5 subunits around one TRPC1 subunit. TRPC1 contributes a unique pore-loop configuration and specialized inter-subunit interfaces that sculpt an asymmetrical ion conduction pathway, altering gating and ion selectivity. The heteromer harbors a ligand-binding pocket at the TRPC1-TRPC5 interface absent in homomeric channels. Using this insight, we design JD03-02, a high-affinity antagonist preferentially targeting this pocket with >10,000-fold selectivity for TRPC1/5 over TRPC5 homomers. In mouse models, JD03-02 produces potent anxiolytic and antidepressant effects with reduced off-target activity. These findings elucidate the structural basis of TRPC1/5 function and can guide precision drug design targeting heteromeric ion channels in neuropsychiatric disorders.

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Publication Details

Journal
Nature Communications
Published
2026-05-23
DOI
https://doi.org/10.1038/s41467-026-73409-1
Primary Topic
Ion Channels and Receptors
Type
article
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0.00
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article

Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects

Xiaojing Song, J Li, Han Hu, Shuqi Zeng et al.
Nature Communications
Ion Channels and Receptors
article

Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects

Xiaojing Song, J Li, Han Hu, Shuqi Zeng, Weiwei Nan, Jingjing Duan, Ougen Liu, Peng Qi, Mingxing Yang, Wei Zhang, Tingting Yang, Sijia Lv, Ye Chen, Yaoguang Hua, Bo Yu, Yinzhen Liu, Jian Li, Jin Zhang, Shuangyan Wan, Xinyu Cheng, Bing Xiong, Yuting Zhang, Xiaoyun Wu, Xiaoqiang Yang, Ying Fu, Tong Che
article en

Abstract

The TRPC1/5 heteromer exhibits electrophysiological and ligand-binding properties distinct from TRPC5 homomers, enabling tissue-specific cellular regulation. Here we present the cryo-EM structure of the TRPC1/5 heterotetramer at 2.8 Å resolution, revealing an asymmetric assembly of three TRPC5 subunits around one TRPC1 subunit. TRPC1 contributes a unique pore-loop configuration and specialized inter-subunit interfaces that sculpt an asymmetrical ion conduction pathway, altering gating and ion selectivity. The heteromer harbors a ligand-binding pocket at the TRPC1-TRPC5 interface absent in homomeric channels. Using this insight, we design JD03-02, a high-affinity antagonist preferentially targeting this pocket with >10,000-fold selectivity for TRPC1/5 over TRPC5 homomers. In mouse models, JD03-02 produces potent anxiolytic and antidepressant effects with reduced off-target activity. These findings elucidate the structural basis of TRPC1/5 function and can guide precision drug design targeting heteromeric ion channels in neuropsychiatric disorders.

Nature Communications
Nanchang University (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Second Affiliated Hospital of Nanchang University (CN), Shanghai Institute of Materia Medica (CN), Gannan Medical University (CN), First Affiliated Hospital of Gannan Medical University (CN), Institute of Aging (CA)
Good health and well-being
Openalex Percentile: Top 6%
Ion Channels and Receptors
DOIOpen Access PDFOpenAlex
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