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Adv."],"published-print":{"date-parts":[[2026,3,27]]},"abstract":"<jats:p>\n                    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\u2019s 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\n                    <jats:italic toggle=\"yes\">Caenorhabditis elegans<\/jats:italic>\n                    induces neurodegeneration, confirming its pathogenicity across species. Cryo\u2013electron 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.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec9284","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:00:16Z","timestamp":1774461616000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Functional and structural basis of a hypermorphic TRPC3 variant"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9797-6402","authenticated-orcid":true,"given":"Briar","family":"Bell","sequence":"first","affiliation":[{"name":"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, 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