WNK1

WNK (lysine deficient protein kinase 1), also known as WNK1, is an enzyme that is encoded by the WNK1

In the

The NKCC1/2 cotransporters are regulated by intracellular Cl⁻ concentration.[9] Studies point to WNK1 as key effector that couples Cl⁻ concentration to NKCC1/2 function.^[5][9] In hypertonic (high extracellular Cl⁻ ) conditions that trigger cell shrinkage, an unknown mechanism upregulates WNK1 expression to counteract the volume loss.^[5] The increased WNK1 leads to activation of SPAK/OSR1 that activate NKCC1/2 via subsequent phosphorylation.^[5][9] NKCC1/2 will promote the influx of Na⁺, K⁺, and Cl⁻ ions into the cell thereby causing the flow of water into the cell.^[5] In the reverse circumstances, where hypotonic (low extracellular Cl⁻ ) conditions induce cell swelling, WNK1 is inhibited.^[5] Another cotransporter, KCC is inactive when phosphorylated; without activated WNK1, KCC does not undergo phosphorylation and can activate.^[5] The cotransporter will promote the efflux of K⁺ and Cl⁻ ions and cause the flow of water out of the cell to combat swelling.^[5]

WNK1 in the brain

In the mature brain, the

Regulation of WNK1

The concentrations of Cl⁻ ions and K⁺ ion play a major role in regulating WNK1 activity.^[5][9] In the DCT, the plasma concentration of K⁺ ion is thought to impact the concentration Cl⁻ ions within the nephron.^[5][9] High plasma K⁺ concentration down regulates WNK1 activity and prevents Cl⁻ ion from entering the nephron via the NCC.^[5][9] The opposite occurs when plasma K⁺ concentration is low; increased WNK1 activity boosts NCC activity promoting reabsorption of Cl⁻ ions.^[5][9] When there is an abundance of Cl⁻ ions within the nephron, WNK1 activity is inhibited by the binding of a Cl⁻ ion to WNK1's catalytic domain.^[5][9]

Furthermore, WNK1 and WNK4 may interact to form heterodimers that inhibit WNK1 function.^[7][6] WNK4 release from the heterodimer allows WNK1 monomer to bind another WNK1 monomer to promote activation.^[6][7] WNK1 function can also be inhibited if WNK1 is degraded. There are two enzymes responsible for WNK1 ubiquitination, kelch like 3 (KLHL3) and cullin 3 (CUL3).^[7][6][10] KLHL3 serves as an adaptor protein that promotes the interaction between WNK1 and Cullin3, which is in a complex containing an E3 ubiquitin ligase that attaches the ubiquitin molecules to WNK1.^[7] The ubiquitinated WNK1 will subsequently undergo proteasomal degradation.^[7][6][10]

Clinical significance

WNK1 has

The gene belongs to a group of four related protein kinases (WNK1, WNK2, WNK3, WNK4).^[5][7][8]

Homologs of this protein have been found in