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.
Acknowledgements
We are grateful to David E. Clapham for critical comments on the manuscript. Our work was supported by School of Basic Medical Sciences, Nanchang University. We would like to thank the Cryo-EM center of The Chinese University of Hong Kong and Shuimu BioSciences Ltd. for the cryo-EM grids screening and data collection. J.Z. was supported by the National Natural Science Foundation of China (grant # 32271260), the CAS “Light of West China” Program (xbzg-zdsys-202005), the Shenzhen Science and Technology Program (grant no. JCYJ20220818103017036 and KJZD20240903102205008) and the Jiangxi Province Natural Science Foundation (grant no. 20224ACB206046). J.L. was supported by the National Natural Science Foundation of China (grant no. 82360701), Jiangxi Province Natural Science Foundation (grant no. 20252BAC250108), Jiangxi “Double Thousand Plan (grant no. jxsq2019101064) and Jiangxi key research and development program (grant no. 20203BBG73063). J.D. was supported by the National Natural Science Foundation of China (grant no. 32471359 and grant no. 82171551). T.C. was supported by Jiangxi Provincial Natural Science Foundation (grant no. 20242BAB20119 and 20252BAC240676). X.S. was supported by the Doctoral Research Startup Fund of Nanchang Medical College (Grant No. NYB22003) and the Research and Technology Project of the Jiangxi Provincial Department of Education (Grant No. GJJ2203514).
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Chen, Y., Che, T., Cheng, X. et al. Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73409-1
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DOI: https://doi.org/10.1038/s41467-026-73409-1
