Functional and structural basis of a hypermorphic TRPC3 variant.
Overview
- Department of Biochemistry and Molecular Biology, Center for Membrane Biology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Molecular Biosciences, University of South Florida, Tampa, FL, USA
- Structural Biology Imaging Center at the University of Texas Health Science Center at Houston, Houston, TX, USA
Abstract
Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific neurodegeneration remain unknown. We uncover how a gain-of-function canonical transient receptor potential member 3 (TRPC3) mutation, coupled with a cerebellum-specific isoform, stabilizes the channel’s open state, resists the leading inhibitor Pyr3, and drives calcium-dependent cell death. Restoring calcium homeostasis by expressing a Purkinje cell calcium pump improves cell viability. Transgenic expression of the TRPC3 hypermorphic variant in Caenorhabditis elegans induces neurodegeneration, confirming its pathogenicity across species. Cryo–electron microscopy and molecular simulations reveal the structural basis for the stabilization of the cerebellar-specific TRPC3 variant in its open state and uncover a druggable allosteric inhibitory binding site. These findings provide an explanation for the vulnerability of cerebellar neurons in TRPC3-associated ataxias and highlight a site for therapeutic intervention.
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Data
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- figshare:29113931, at figshare; found in “Data, code, and materials availability:”
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Versions
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 10 MeSH terms, 4 funders, 82 references.
Cite
This paper
Bell, B., Jaramillo-Granada, A. M., Romero, L. O., Gutierrez, I. A., Mallampalli, V. K., Fan, G., Varma, S., Baker, M. L., Serysheva, I. I., Vásquez, V., & Cordero-Morales, J. F. (2026). Functional and structural basis of a hypermorphic TRPC3 variant. Science advances, 12(13), eaec9284. https://
BibTeX
@article{bell2026functio
author = {Bell, Briar and Jaramillo-Granada, Angela M and Romero, Luis O and Gutierrez, Irene A and Mallampalli, Venkata KPS and Fan, Guizhen and Varma, Sameer and Baker, Matthew L and Serysheva, Irina I and Vásquez, Valeria and Cordero-Morales, Julio F},
title = {{Functional and structural basis of a hypermorphic TRPC3 variant}},
journal = {Science advances},
year = {2026},
month = mar,
volume = {12},
number = {13},
pages = {eaec9284},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/
url = {https://
pmid = {41880503},
pmcid = {PMC13015894}
}
RIS
TY - JOUR
AU - Bell, Briar
AU - Jaramillo-Granada, Angela M
AU - Romero, Luis O
AU - Gutierrez, Irene A
AU - Mallampalli, Venkata KPS
AU - Fan, Guizhen
AU - Varma, Sameer
AU - Baker, Matthew L
AU - Serysheva, Irina I
AU - Vásquez, Valeria
AU - Cordero-Morales, Julio F
TI - Functional and structural basis of a hypermorphic TRPC3 variant
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/
VL - 12
IS - 13
SP - eaec9284
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/
UR - https://
LA - en
ER -
CSL-JSON
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