Similar effects of all WNK3 variants on SLC12 cotransporters.

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Cruz-Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla NA, Pasantes-Morales H, Gamba G, Mercado A

Similar effects of all WNK3 variants on SLC12 cotransporters.

Am J Physiol Cell Physiol. 2011 Sep;301(3):C601-8. doi: 10.1152/ajpcell.00070.2011. Epub 2011 May 25.

PubMed ID
21613606 [ View in PubMed
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Abstract

With-no-lysine kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18a+22, 18b, and 18b+22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Solute carrier family 12 member 5Q9H2X9Details
Solute carrier family 12 member 6Q9UHW9Details
Solute carrier family 12 member 7Q9Y666Details
Solute carrier family 12 member 2P55011Details
Solute carrier family 12 member 3P55017Details
Solute carrier family 12 member 1Q13621Details
Solute carrier family 12 member 4Q9UP95Details