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

AUTOR(ES)

Raghuram, Viswanathan

FONTE

National Academy of Sciences

RESUMO

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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