期刊
EMBO REPORTS
卷 23, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/embr.202154276
关键词
diacylglycerol; lipid regulation; lipid-protein interactions; TRPC channels
资金
- FWF [P33263, P35291]
- Austrian Science Fund (FWF) [P33263, P35291] Funding Source: Austrian Science Fund (FWF)
Coordination of lipids within TRPCs channels is crucial for their Ca2+ signaling function. Researchers identified two lipid interaction sites, L1 and L2, which rapidly accumulate diacylglycerols (DAGs) and enhance TRPC3 currents.
Coordination of lipids within transient receptor potential canonical channels (TRPCs) is essential for their Ca2+ signaling function. Single particle cryo-EM studies identified two lipid interaction sites, designated L1 and L2, which are proposed to accommodate diacylglycerols (DAGs). To explore the role of L1 and L2 in TRPC3 function, we combined structure-guided mutagenesis and electrophysiological recording with molecular dynamics (MD) simulations. MD simulations indicate rapid DAG accumulation within both L1 and L2 upon its availability within the plasma membrane. Electrophysiological experiments using a photoswitchable DAG-probe reveal potentiation of TRPC3 currents during repetitive activation by DAG. Importantly, initial DAG exposure generates a subsequently sensitized channel state that is associated with significantly faster activation kinetics. TRPC3 sensitization is specifically promoted by mutations within L2, with G652A exhibiting sensitization at very low levels of active DAG. We demonstrate the ability of TRPC3 to adopt a closed state conformation that features partial lipidation of L2 sites by DAG and enables fast activation of the channel by the phospholipase C-DAG pathway.
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