The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases

Abstract

In recent years, cation-chloride cotransporters (CCCs) have drawn attention in the medical neuroscience research. CCCs include the family of Na + -coupled Cl - importers (NCC, NKCC1, and NKCC2), K + -coupled Cl - exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC interacting protein (CIP1). For decades, CCCs have been the targets of several commonly used diuretic drugs, including hydrochlorothiazide, furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause congenital renal tubular disorders and lead to renal salt-losing hypotension, secondary hyperreninemia, and hypokalemic metabolic alkalosis. New studies reveal that CCCs along with their regulatory WNK (Kinase with no lysine (K)), and SPAK (Ste20-related proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1) are essential for regulating cell volume and maintaining ionic homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl - exporter KCC2 has an effect on synaptic inhibition, which may be involved in developing pain, epilepsy, and possibly some neuropsychiatric disorders. Interference with KCC3 leads to peripheral nervous system neuropathy as well as axon and nerve fiber swelling and psychosis. The WNK-SPAK/OSR1-CCCs complex emerges as therapeutic targets for multiple neurological diseases. This review will highlight these new findings.

Ketogenic Diet Provided During Three Months Increases KCC2 Expression but Not NKCC1 in the Rat Dentate Gyrus

“…However, future studies should be conducted to explore the effect of a ketogenic diet on NKCC1 and KCC2 phosphorylation by WNK-SPAK/OSR1 pathway [WNK (kinase with no lysine (K)), SPAK (STE20-related proline-alanine-rich kinase) as well as OSRI (oxidative stress-responsive kinasa-1)], their upstream regulatory serine-threonine kinases. WNK kinases are not only effector kinases that work in conjunction with the SPAK/OSR1 kinases to regulate cation-chloride cotransporters by phosphorylation, but may also serve as intracelular Cl – sensors ( Moriguchi et al, 2005 ; Arroyo et al, 2013 ; Huang et al, 2019 ).…”

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

“…However, the implication of the interaction between KCC2 and CKB in relation to their physiological functions and how intracellular ATP concentrations might contribute to KCC2 function is still elusive [80]. More importantly, however, the fact that WNK-SPAK/OSR1 kinase complex is known to phosphorylate and inhibit KCC2 or stimulate NKCC1 [52,[64][65][66][67] is already established. Thus, molecular compounds that can block WNK-SPAK/OSR1 signalling pathway will result in activating KCC2 and inhibiting NKCC1 activities.…”

“…Since the healthy brain relies on the proper balance between excitatory and inhibitory inputs, uncontrolled regulation of neuronal excitability can have implications for health [32]. Neuronal [Cl − ] i is largely regulated through the activity of Na + -K + -2Cl − cotransporter 1 (NKCC1) and KCC2 [51][52][53]. NKCC1 pumps Cl − into neurons, while KCC2 is responsible for Cl − efflux [50,53].…”

“…However, during maturation, NKCC1 expression gradually decreases, and KCC2 expression increases, resulting in an opposite expression pattern [50,63] (also see Figure 2). Importantly, the inhibition/stimulation of KCC2/NKCC1 pair via protein phosphorylation is through a regulatory mechanism that works in a reciprocal pattern [53,64] and members of the with-no-lysine kinase (WNKs) family as well as their downstream targets; STE20/SPS1-related proline/alanine rich kinase (SPAK) and oxidative stress response kinase (OSR1) are the most prominent kinases that regulate this process [52,[64][65][66][67]. Consequently, impaired ion homeostasis resulting from mutation in the physiological function of some of this transporter pair and/or their upstream regulators may be detrimental and subsequently result in diminished inhibition and augmented network hyperexcitability, which underlies numerous neurological disorders [52,66,[68][69][70][71] including HD [58][59][60].…”

NKCC1 modulates microglial phenotype, cerebral inflammatory responses and brain injury in a cell-autonomous manner

“…Both transporters contribute to broad and heterogenous biological processes, including cell volume regulation, neuronal development, maturation and synapse formation, while they are also essential to sustain low intracellular Cllevels in mature neurons (Ben-Ari, 2002;Kaila et al, 2014;Rivera et al, 1999;Yamada et al, 2004). NKCC1 is implicated in a number of neuropathological conditions, including neonatal seizures, temporal lobe epilepsy, autism spectrum disorders, schizophrenia, and brain edema after traumatic or hypoxic/ischaemic injury (Garneau et al, 2020;Huang et al, 2019b;Kahle et al, 2008;Kaila et al, 2014). However, the cellular targets for central NKCC1 actions remain to be characterized.…”