Functional and structural basis of a hypermorphic TRPC3 variant - PubMed
3 hours ago
- #Cerebellar Ataxia
- #Calcium Homeostasis
- #TRPC3
- Cerebellar ataxias result from impaired motor coordination due to neuronal dysfunction in the cerebellum.
- A gain-of-function TRPC3 mutation stabilizes the channel's open state, resists inhibitor Pyr3, and causes calcium-dependent cell death.
- Expressing a Purkinje cell calcium pump restores calcium homeostasis and improves cell viability.
- Transgenic expression of the TRPC3 variant in C. elegans confirms its pathogenicity across species.
- Cryo-EM and molecular simulations reveal structural basis for the open state stabilization and identify a druggable allosteric inhibitory site.
- Findings explain cerebellar neuron vulnerability in TRPC3-associated ataxias and highlight therapeutic intervention potential.