title: The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.
abstract: The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Khanna
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hochdörfer
authors.affiliation: Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yuze
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02115, USA. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. kkahle@enders.tch.harvard.edu.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
mesh_terms: D001665:Binding Sites / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D028021:Sodium-Potassium-Chloride Symporters; C118135:OXSR1 protein, human; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human