Abstract
The role of Cl– as an intracellular signaling ion has been increasingly recognized in recent years. One of the currently best described roles of Cl– in signaling is the modulation of the With-No-Lysine (K) (WNK) – STE20-Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1) – Cation-Coupled Cl– Cotransporters (CCCs) cascade. Binding of a Cl– anion to the active site of WNK kinases directly modulates their activity, promoting their inhibition. WNK activation due to Cl– release from the binding site leads to phosphorylation and activation of SPAK/OSR1, which in turn phosphorylate the CCCs. Phosphorylation by WNKs-SPAK/OSR1 of the Na+-driven CCCs (mediating ions influx) promote their activation, whereas that of the K+-driven CCCs (mediating ions efflux) promote their inhibition. This results in net Cl– influx and feedback inhibition of WNK kinases. A wide variety of alterations to this pathway have been recognized as the cause of several human diseases, with manifestations in different systems. The understanding of WNK kinases as Cl– sensitive proteins has allowed us to better understand the mechanistic details of regulatory processes involved in diverse physiological phenomena that are reviewed here. These include cell volume regulation, potassium sensing and intracellular signaling in the renal distal convoluted tubule, and regulation of the neuronal response to the neurotransmitter GABA.
Highlights
Specialty section: This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology
These include cell volume regulation, potassium sensing and intracellular signaling in the renal distal convoluted tubule, and regulation of the neuronal response to the neurotransmitter GABA
Subsequent targeted knockout experiments in the same model showed that WNK3 knockout, and WNK1 knockout decreased KCC3 and NKCC1 phosphorylation in this model. They showed that HEK293 cells expressing KCC3 and transiently transfected with wild type WNK3 swelled under hypotonic stimulation, while expression of WNK3-KD prevented hypotonic swelling
Summary
The chloride (Cl−) anion is an important component of all known living beings, where it plays several roles in homeostatic and rheostatic processes in all types of cells. [Cl−]i can be dynamically modulated by different stimuli, such as cholinergic agonists (Foskett, 1990), cAMP levels (Xie and Schafer, 2004), lectin-stimulation (Lai et al, 2003), and extracellular potassium concentration ([K+]e) (Terker et al, 2015b) These reports exemplify the wide variation of [Cl−]i, which is important for the role that this anion plays in the physiology of specific cell types. Secondary active transporters can set the [Cl−]i at levels that diverge from the electrochemical equilibrium by coupling Na+ influx or K+ efflux to the movement of Cl− Transporters with this type of activity are all members of the SLC12 family of solute carriers described below. The major physiological roles of the CCCs are modulation of [Cl−]i, cell volume regulation, and transepithelial ion transport.
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