Editors' ChoiceCell Biology

New connections: NHERF gates activity

Sci. Signal.  10 Jan 2017:
Vol. 10, Issue 461,
DOI: 10.1126/scisignal.aam7242

The NHERF molecular adaptors serve as gates for TRPC4 and TRPC5 regulation by diacylglycerol and recognition of CFTR by the quality control checkpoint.

Proteins in the NHERF family are adaptor proteins with PDZ protein interaction domains. The transient receptor potential (TRP) family of channels has two members with PDZ binding motifs, TRPC4 and TRPC5. These two TRPC channels are important in regulating neuronal excitability, have been implicated in epilepsy, and have been associated with a protective function in the kidney. Storch et al. found that these two TRPC channels interacted with NHERF proteins and that disrupting this interaction in transfected cells by knockdown or expression of mutant forms of the proteins that could not interact enabled activation of TRPC4 or TRPC5 by the diacylglycerol analog OAG. Furthermore, coexpression with Gq/11-coupled receptors, such as muscarinic acetylcholine receptors or histamine receptors; inhibition of protein kinase C (PKC); or depletion of phosphatidylinositol-3,4-bisphosphate (PIP2) also enabled activation of the channel by OAG. Substitution of a putative PKC phosphorylation site in the PDZ binding domain of TRPC5 to an alanine resulted in OAG-mediated enhancement of TRPC5 activity without the requirement of PKC inhibition or activation of a Gq/11-coupled receptor, whereas substitution with phosphorylation-mimicking residues blocked sensitivity to OAG. Fluorescence resonance energy transfer assays indicated that conditions that enabled OAG regulation of TRPC5 altered the conformation of the C-terminal part of TRPC5 and disrupted the interaction between NHERF1 and the channel. In a study by Loureiro et al., drugs that promoted the interaction between NHERF1 and the cytoskeleton protected partially functional CTFR (the transporter protein that causes cystic fibrosis) from binding to proteins that trigger the removal of misfolded proteins from the membrane. When NHERF1 interacted with the cytoskeleton, a second PDZ domain was exposed enabling the interaction with CTFR. Thus, combining drugs that promote the interaction between NHERF1 and the cytoskeleton with drugs that increase the trafficking of partially functional CFTR could improve cystic fibrosis treatment. Collectively, these studies indicate that through interactions mediated by its PDZ domain, NHERF1 serves as a gatekeeper: limiting the regulation of TRPC4 and TRPC5 channels by diacylglycerol until the right conditions are met and blocking access to the peripheral quality control machinery for CFTR.

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