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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)
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
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
Language
Publication Year
2017
Prepublished in Year
2016
HGF-reported in Year
2016
ISSN (print) / ISBN
0027-8424
e-ISSN
1091-6490
Quellenangaben
Volume: 114,
Issue: 1,
Pages: E37-E46
Publisher
National Academy of Sciences
Publishing Place
Washington
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Lung Research
PSP Element(s)
G-505000-006
WOS ID
WOS:000391093700005
PubMed ID
27994151
Erfassungsdatum
2016-12-31