The activity of the thiazide-sensitive Na+–Cl cotransporter is regulated by protein phosphatase PP4

M Glover, A Mercier Zuber, N Figg… - Canadian journal of …, 2010 - cdnsciencepub.com
M Glover, A Mercier Zuber, N Figg, KM O'Shaughnessy
Canadian journal of physiology and pharmacology, 2010cdnsciencepub.com
Cation transport in the distal mammalian nephron relies on the SLC12 family of membrane
cotransporters that include the thiazide-sensitive Na+–Cl–cotransporter (NCC). NCC is
regulated through a scaffold of interacting proteins, including the WNK kinases, WNK 1 and
WNK 4, which are mutated in the hypertensive Gordon's syndrome. Dynamic regulation of
NCC function by kinases must involve dephosphorylation by phosphatases, as illustrated by
the role of PP1 and PP2B in the regulation of KCC members of the SLC12 family. There are …
Cation transport in the distal mammalian nephron relies on the SLC12 family of membrane cotransporters that include the thiazide-sensitive Na+–Cl cotransporter (NCC). NCC is regulated through a scaffold of interacting proteins, including the WNK kinases, WNK 1 and WNK 4, which are mutated in the hypertensive Gordon’s syndrome. Dynamic regulation of NCC function by kinases must involve dephosphorylation by phosphatases, as illustrated by the role of PP1 and PP2B in the regulation of KCC members of the SLC12 family. There are 2 phosphorylation-controlled regulatory pathways for NCC: type 1, mediated by WNK4 and affecting trafficking to the surface membrane, and type 2, affecting intrinsic transporter kinetics by phosphorylation of conserved N-terminal S/T amino acids. Using the Xenopus oocyte expression system, we show that PP4 inhibits NCC activity — but not trafficking to the surface membrane — by a mechanism that requires phosphatase activity and a conserved N-terminal amino acid of NCC, threonine 58. This action is distinct from WNK4 regulation of membrane trafficking. In the mouse kidney, PP4 is selectively expressed in the distal nephron, including cells of the distal convoluted tubule cells, suggesting that PP4 may have a physiological role in regulating NCC and hence NaCl reabsorption in vivo.
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