WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.

Abstract

Loss of physiological regulation of the renal thiazide-sensitive Na+-Cl- cotransporter (NCC) by mutant WNK1 or WNK4 results in pseudohypoaldosteronism type II (PHAII) characterized by arterial hypertension and hyperkalemia. WNK4 normally inhibits NCC, but this effect is lost by eliminating WNK4 catalytic activity or through PHAII-type mutations. In contrast, another member of the WNK family, WNK3, activates NCC. The positive effect of WNK3 on NCC also requires its catalytic activity. Because the opposite effects of WNK3 and WNK4 on NCC were observed in the same expression system, sequences within the WNKs should endow these kinases with their activating or inhibiting properties. To gain insight into the structure-function relationships between the WNKs and NCC, we used a chimera approach between WNK3 and WNK4 to elucidate the domain of the WNKs responsible for the effects on NCC. Chimeras were constructed by swapping the amino or carboxyl terminus domains, which flank the central kinase domain, between WNK3 and WNK4. Our results show that the effect of chimeras toward NCC follows the amino-terminal domain. Thus the amino terminus of the WNKs contains the sequences that are required for their activating or inhibiting properties on NCC.

• Authors: Pedro San-Cristobal, José Ponce-Coria, Norma Vázquez, Norma A Bobadilla, Gerardo Gamba
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 295 Issue 4 Pg. F1199-206 (Oct 2008) ISSN: 1931-857X [Print] United States
• PMID: 18701621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mutant Chimeric Proteins
• Receptors, Drug
• Sodium Chloride Symporters
• Symporters
• potassium-chloride symporters
• thiazide receptor
• Prkwnk4 protein, mouse
• Protein Serine-Threonine Kinases
• WNK3 protein, human

Topics

• Animals
• Catalysis
• Humans
• Hypertension, Renal (metabolism, physiopathology)
• Kidney Tubules, Distal (physiology)
• Mice
• Mutant Chimeric Proteins
• Oocytes (physiology)
• Protein Serine-Threonine Kinases (chemistry, genetics, metabolism)
• Protein Structure, Tertiary
• Pseudohypoaldosteronism (metabolism, physiopathology)
• Rats
• Receptors, Drug (genetics, metabolism)
• Sodium Chloride Symporters (genetics, metabolism)
• Structure-Activity Relationship
• Symporters (genetics, metabolism)
• Xenopus laevis