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The Carboxyl Terminus of WNK4 Suppresses Forward Trafficking of the Thiazide‐Sensitive Cotransporter
Author(s) -
Subramanya Arohan R.,
Wade James B.,
Ellison David H.,
Welling Paul A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1337-a
Subject(s) - internalization , cotransporter , brefeldin a , microbiology and biotechnology , chemistry , endocytosis , reabsorption , symporter , cell , biochemistry , biology , transporter , sodium , golgi apparatus , organic chemistry , gene
WNK4 kinase has been proposed to act as a switch that coordinates NaCl and K + handling in the distal nephron. This hypothesis is based on observations that the kinase inhibits the cell surface expression of the thiazide‐sensitive cotransporter (NCC) and the potassium channel Kir 1.1 (ROMK). While WNK4 reduces ROMK surface density by enhancing channel internalization, details regarding the other component of the switch, NCC, remain unresolved. Here, we used 22 Na + transport measurements in X. laevis oocytes and surface luminescence assays in mammalian cells to study WNK4 effects on NCC trafficking. An analysis of the cell surface lifetime of NCC in the presence of brefeldin A (BFA), a reversible inhibitor of exocytosis, showed that WNK4 did not accelerate the rate of NCC internalization. In contrast, forward trafficking time courses revealed that the recovery of cotransporter activity following release from BFA‐induced intracellular retention was completely blunted in the presence of the kinase (2 × 30 oocytes/time point, p=0.0028). Mutagenesis studies indicated that a C‐terminal coiled‐coil domain‐containing region mediates the suppressive effect. Taken together, these data suggest that the WNK4 C‐terminus suppresses NCC surface expression by reducing its cell surface delivery. Thus, WNK4 may control renal NaCl reabsorption and K + secretion by coordinating NCC forward trafficking and ROMK endocytosis.

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