Cullin3/WNK/SPAK Signaling: Impact on NaCl Cotransporter Activity in Blood Pressure Regulation.

Abstract

The sodium chloride co-transporter (NCC) fine-tunes Na+ balance and indirectly affects the homeostasis of other ions including K+, Mg2+ and Ca2+. Due to its effects on Na+ balance, blood pressure is significantly affected by alterations in NCC activity. Several factors have been reported to influence the expression and activity of NCC. One critical factor is NCC phosphorylation/dephosphorylation that occurs at key serine-threonine amino acid residues of the protein. Phosphorylation, which results in increased NCC activity, is mediated by the WNK-SPAK/OSR1 kinases. NCC activation stimulates reabsorption of Na+, increasing extracellular fluid volume and hence blood pressure. On the other hand, proteasomal degradation of WNK kinases following ubiquitination by the CUL3-KLHL3 E3 ubiquitin ligase complex and dephosphorylation pathways oppose WNK-SPAK/OSR1-mediated NCC activation. Components of the CUL3/KLHL3-WNK-SPAK/OSR1 regulatory pathway may be targets for novel anti-hypertensive drugs. In this review, we outline the impact of these regulators on the activity of NCC and the consequent effect on blood pressure.