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Diacylglycerols interact with the L2 lipidation site in TRPC3 to induce a sensitized channel state
Author(s) -
ErkanCandag Hazel,
Clarke Amy,
Tiapko Oleksandra,
Gsell Mathias AF,
Stockner Thomas,
Groschner Klaus
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202154276
Subject(s) - trpc3 , diacylglycerol kinase , biophysics , transient receptor potential channel , chemistry , lipid anchored protein , visual phototransduction , mutagenesis , electrophysiology , biochemistry , microbiology and biotechnology , biology , signal transduction , mutation , receptor , trpc , neuroscience , apoptosis , protein kinase c , autophagy , gene , retinal
Coordination of lipids within transient receptor potential canonical channels (TRPCs) is essential for their Ca 2+ 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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