A kinase-regulated mechanism controls CFTR channel gating by disrupting bivalent PDZ domain interactions

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Abstract

Dynamic regulation of ion channels is critical for maintaining fluid balance in epithelial tissues. Cystic fibrosis, a genetic disease characterized by impaired fluid transport in epithelial tissues, is caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel activity. Recent studies have shown that binding of PSD-95/Dlg/ZO-1 (PDZ) domain proteins to CFTR is important for retaining it at the apical membrane and for regulating its channel activity. Here, we describe a phosphorylation mechanism that regulates CFTR channel activity, which is mediated by PDZ domains. The Na+/H+ exchanger regulatory factor (NHERF) binds to CFTR and increases its open probability (Po). Protein kinase C disrupts the stimulatory effect of NHERF on CFTR channel Po. Phosphorylation by PKC of Ser-162 in the PDZ2 domain of NHERF is critical for this functional effect. Furthermore, a mutation in PDZ2 that mimics phosphorylation decreases CFTR binding and disrupts the ability of NHERF PDZ1-2 to stimulate CFTR channel Po. Our results identify a role for PKC and suggest that phosphorylation of NHERF PDZ2 domain may be an important mechanism for regulating CFTR channel activity.

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Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction.

Y Hayashi, S. Shi, J. Esteban … (2000)

To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.

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PDZ domains and the organization of supramolecular complexes.

M. Sheng, C Sala (2001)

PDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a beta-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell.