Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters.

Sodium and chloride transport play a fundamental role in many physiological processes. In the kidney, sodium secretion and reabsorption are essential to maintain the extracellular volume and, thus, blood pressure (BP). In vascular smooth muscle, it is important for contractility and in the nervous system for the functioning of GABAergic neurons. Hence, the emergence of a WNK/SPAK/OSR1 kinase cascade that activates NaCl cotransporters has widespread physiological implications. This review gives an overview of the actions of SPAK and OSR1 kinases on NaCl cotransporters and highlights their possible therapeutic potential. Evidence has emerged from in-vitro phosphorylation assays that WNK kinases can activate SPAK and OSR1 kinases by phosphorylation of a key Thr residue in their catalytic domains. Once activated, SPAK and OSR1 in turn activate members of the SCL12A family of solute carriers by phosphorylation of conserved Ser/Thr residues in the N-terminal domain of these carrier proteins. The importance of this pathway has recently emerged from studies on mice that lack a catalytically active SPAK enzyme. These models are strikingly hypotensive with marked reduction in the phosphorylation of Na⁺/Cl⁻ cotransporter (NCC) in the kidney, and reduced Na⁺/K⁺/2Cl⁻ cotransporter (NKCC1) phosphorylation in the vessel wall. SPAK and OSR1 kinases regulate SCL12A transporters with important physiological effects for sodium homeostasis by the kidney, aortic contractility and neuronal excitability. In vivo, SPAK plays a major role in the regulation of blood pressure and represents a potential target for the development of novel diuretics.