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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lichtenegger, M; Tiapko, O; Svobodova, B; Stockner, T; Glasnov, TN; Schreibmayer, W; Platzer, D; de la Cruz, GG; Krenn, S; Schober, R; Shrestha, N; Schindl, R; Romanin, C; Groschner, K.
An optically controlled probe identifies lipid-gating fenestrations within the TRPC3 channel.
Nat Chem Biol. 2018; 14(4):396-404
Doi: 10.1038/s41589-018-0015-6
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- Führende Autor*innen der Med Uni Graz
- Groschner Klaus
- Lichtenegger Michaela
- Co-Autor*innen der Med Uni Graz
- Platzer Dieter
- Schindl Rainer
- Schreibmayer Wolfgang
- Shrestha Niroj
- Svobodova Barbora
- Tiapko Oleksandra
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- Abstract:
- Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light. A structure-guided mutagenesis screen of the TRPC3 pore domain unveiled a single glycine residue behind the selectivity filter (G652) that is exposed to lipid through a subunit-joining fenestration. Exchange of G652 with larger residues altered the ability of TRPC3 to discriminate between different DAG molecules. Light-controlled activation-deactivation cycling of TRPC3 channels by an OptoDArG-mediated optical 'lipid clamp' identified pore domain fenestrations as pivotal elements of the channel´s lipid-sensing machinery. We provide evidence for a novel concept of lipid sensing by TRPC channels based on a lateral fenestration in the pore domain that accommodates lipid mediators to control gating.