Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol
| Autor: | Manuel Gregoritza, Maximilian Philipp, Ursula Storch, Michael Mederos y Schnitzler, Serap Erdogmus, Thomas Gudermann, Franziska Pardatscher, Anna-Lena Forst |
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| Rok vydání: | 2016 |
| Předmět: |
Diacylglycerol
Nherf Trpc Pip2 Depletion Protein Interaction 0301 basic medicine Scaffold protein Sodium-Hydrogen Exchangers Multidisciplinary Chemistry Phosphoproteins TRPC5 TRPC4 Diglycerides 03 medical and health sciences Transient receptor potential channel 030104 developmental biology PNAS Plus Biochemistry Biophysics lipids (amino acids peptides and proteins) Signal transduction Protein kinase C TRPC Diacylglycerol kinase |
| Zdroj: | Proc. Natl. Acad. Sci. U.S.A. 114, E37-E46 (2017) |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1612263114 |
| Popis: | The activation mechanism of the classical transient receptor potential channels TRPC4 and -5 via the G(q/11) protein-phospholipase C (PLC) signaling pathway has remained elusive so far. In contrast to all other TRPC channels, the PLC product diacylglycerol (DAG) is not sufficient for channel activation, whereas TRPC4/5 channel activity is potentiated by phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. As a characteristic structural feature, TRPC4/5 channels contain a C-terminal PDZ-binding motif allowing for binding of the scaffolding proteins Na+/H+ exchanger regulatory factor (NHERF) 1 and 2. PKC inhibition or the exchange of threonine for alanine in the C-terminal PDZ-binding motif conferred DAG sensitivity to the channel. Altogether, we present a DAG-mediated activation mechanism for TRPC4/5 channels tightly regulated by NHERF1/2 interaction. PIP2 depletion evokes a C-terminal conformational change of TRPC5 proteins leading to dynamic dissociation of NHERF1/2 from the C terminus of TRPC5 as a prerequisite for DAG sensitivity. We show that NHERF proteins are direct regulators of ion channel activity and that DAG sensitivity is a distinctive hallmark of TRPC channels. |
| Databáze: | OpenAIRE |
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