The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters
Gloss
Intracellular chloride concentration is critical in the maintenance of cellular volume and the regulation of neuronal activity and blood pressure. Because of its therapeutic importance, several drugs exist that target cotransporters of the regulated Cl− transport, especially the cotransporters in the kidney. In this Review, with five figures and 115 references, Alessi et al. describe the genetic and biochemical experiments that led to the discovery of the molecular components involved in this essential physiological regulatory pathway that controls intracellular Cl− concentration. Knowledge of the proteins, how they interact, and the regulatory mechanisms that control their activity presents novel targets for controlling hypertension and intervening in neurological diseases associated with excess neuronal activity.
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.
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Published In
Science Signaling
Volume 7 | Issue 334
July 2014
July 2014
Copyright
Copyright © 2014, American Association for the Advancement of Science.
Submission history
Received: 11 April 2014
Accepted: 25 June 2014
Acknowledgments
D.R.A. research in this area is supported by the Medical Research Council and the Wellcome Trust (grant number 091415) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck KGaA, Janssen Pharmaceutica, and Pfizer). K.T.K. is supported by the Manton Center for Orphan Diseases at Boston Children’s Hospital at Harvard Medical School, and the Harvard/MIT Joint Research Grants Program in Basic Neuroscience.
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