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Storch, U.* ; Forst, A.* ; Pardatscher, F.* ; Erdogmus, S.* ; Philipp, M.* ; Gregoritza, M.* ; Mederos y Schnitzlera, M.* ; Gudermann, T.

Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol.

Proc. Natl. Acad. Sci. U.S.A. 114, E37-E46 (2017)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Diacylglycerol ; Nherf ; Trpc ; Pip2 Depletion ; Protein Interaction; Exchanger Regulatory Factor; Pdz Scaffold Nherf-2; Phosphatidylinositol 4,5-bisphosphate; Cation Channel; Kinase-c; Beta(2)-adrenergic Receptor; Induced Cytotoxicity; Ion-transport; Ca2+ Influx; Cell-lines
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 114, Issue: 1, Pages: E37-E46 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place Washington
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)