Back to Search
Start Over
Transient receptor potential canonical type 6 (TRPC6) O-GlcNAcylation at Threonine-221 plays potent role in channel regulation.
- Source :
-
IScience [iScience] 2023 Feb 28; Vol. 26 (3), pp. 106294. Date of Electronic Publication: 2023 Feb 28 (Print Publication: 2023). - Publication Year :
- 2023
-
Abstract
- Transient receptor potential canonical type 6 (TRPC6) is a non-voltage-gated channel that principally conducts calcium. Elevated channel activation contributes to fibrosis, hypertrophy, and proteinuria, often coupled to stimulation of nuclear factor of activated T-cells (NFAT). TRPC6 is post-translationally regulated, but a role for O-linked β-N-acetyl glucosamine (O-GlcNAcylation) as elevated by diabetes, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated at Ser14, Thr70, and Thr221 in the N-terminus ankryn-4 (AR4) and linker (LH1) domains. Mutagenesis to alanine reveals T221 as a critical controller of resting TRPC6 conductance, and associated NFAT activity and pro-hypertrophic signaling. T→A mutations at sites homologous in closely related TRPC3 and TRPC7 also increases their activity. Molecular modeling predicts interactions between Thr221- O -GlcNAc and Ser199, Glu200, and Glu246, and combined alanine substitutions of the latter similarly elevates resting NFAT activity. Thus, O-GlcNAcylated T221 and interactions with coordinating residues is required for normal TRPC6 channel conductance and NFAT activation.<br />Competing Interests: D.A.K. receives grant support from Boehringer Ingelheim pursuing the use of a selective TRPC6 antagonist for treatment of Duchenne Muscular Dystrophy.<br /> (© 2023 The Authors.)
Details
- Language :
- English
- ISSN :
- 2589-0042
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- IScience
- Publication Type :
- Academic Journal
- Accession number :
- 36936781
- Full Text :
- https://doi.org/10.1016/j.isci.2023.106294