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Aging and disease    2019, Vol. 10 Issue (3) : 626-636     DOI: 10.14336/AD.2018.0928
Review |
The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases
Huachen Huang1,2, Shanshan Song2, Suneel Banerjee2, Tong Jiang2, Jinwei Zhang3, Kristopher T. Kahle4, Dandan Sun2,5,*, Zhongling Zhang1,*
1 Department of Neurology, The First Affiliate Hospital, Harbin Medical University, Harbin, Heilongjiang, China.
2Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
3Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, EX4 4PS, UK.
4Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, USA.
5Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Education and Clinical Center, Pittsburgh, PA, USA.
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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.

Keywords brain edema      cell volume regulation      ischemic stroke      KCCs      NKCC1      WNK-SPAK/OSR1     
Corresponding Authors: Sun Dandan,Zhang Zhongling   
About author:

These authors contributed equally to this work.

Just Accepted Date: 02 October 2018   Issue Date: 28 May 2019
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Huachen Huang
Shanshan Song
Suneel Banerjee
Tong Jiang
Jinwei Zhang
Kristopher T. Kahle
Dandan Sun
Zhongling Zhang
Cite this article:   
Huachen Huang,Shanshan Song,Suneel Banerjee, et al. The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases[J]. Aging and disease, 2019, 10(3): 626-636.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0928     OR     http://www.aginganddisease.org/EN/Y2019/V10/I3/626
ProteinCo-transport ionsTissue and Subcellular DistributionRelating to human diseasesPhenotypes of KO/KI miceRefs.
SLC12A1 (NKCC2)Na+, K+, Cl-Kidney-specific (TAL);
apical plasma membrane; hypothalamo-neurohypophyseal system
Bartter syndromeSevere hypotension, hypokalemia,
hypercalciuria, metabolic alkalosis
[80-82]
SLC12A2 (NKCC1)Na+, K+, Cl-Ubiquitous;
basolateral plasma membrane
NoneSensorineural deafness,
alterations in endolymph secretion, reduced saliva production, sensory perception abnormalities and infertility
[58, 83-86]
SLC12A3 (NCC)Na+, Cl-Kidney-specific (DCT);
bone? apical plasma membrane
Gitelman
syndrome
Hypotension, hypocalciuria, hypomagnesemia, hypokalemia[87-89]
SLC12A4 (KCC1)K+, Cl-UbiquitousNoneNo phenotype[90]
SLC12A5 (KCC2)K+, Cl-Neuron-specific;
basolateral plasma membrane (?)
EpilepsyComplete - death due to absent respiratory drive.
Incomplete KO (5%of function remains). Status epilepticus, death ± 15 days after birth.
[91, 92]
SLC12A6 (KCC3)K+, Cl-WidespreadAndermann syndromeKnockout mice recapitulate the
locomotion and neuropathy phenotypes and demonstrate axonal swelling
[92, 93]
SLC12A7 (KCC4)K+, Cl-Widespread;
basolateral plasma membrane (?)
NoneSensorineural deafness
and renal tubular acidosis
[94, 95]
SPAK--UbiquitousNo report in human, but resemble Gitelman syndrome in miceKO mice exhibited hypotension and recapitulated Gitelman syndrome with hypokalemia, hypomagnesemia, and hypocalciuria; higher nociceptive threshold and increased anxiety[12, 66]
OSR1--UbiquitousNo report in human, but resemble Bartter syndrome in miceGlobal KO - die in utero. Heterozygous KO - low BP. Kidney tubule-specific KO - normal BP with hypercalciuria and hypokalemia[96, 97]
WNK1--UbiquitousHSANⅡ;
PHAII
Less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury[73, 75, 96, 98, 99]
WNK2--Prominently expressed in brain neurons; fetal brain and heartNo reportNo report[100, 101]
WNK3--UbiquitousAutistic disorder?Mice exhibited less cytotoxic edema after MCAO; compensated elevation of WNK1/SPAK axis in the kidney[34, 65, 72, 102]
WNK4--UbiquitousPHAIIKO mice exhibited hypokalemia but normalcalciuria[99, 103]
Table 1  Phenotypes of transgenic knockout (KO) mice involving WNK-SPAK/OSR1-CCC complex
Figure 1.  Roles of CCC in cell volume regulation

Intracellular osmolarity changes trigger cellular responses for volume regulation. Under hypertonic extracellular conditions, water extrudes from the cells and causes cell shrinkage, triggering a counter-response of regulatory volume increase (RVI). In this condition, the WNK-SPAK/OSR1 pathway is activated and phosphorylates NKCC1 and KCCs, resulting in NKCC1activation and KCCs inhibition. This subsequently leads to influx of Na+, K+ and Cl- via NKCC1 along with water, thus restoring cell volume. On the contrary, cell swelling due to hypotonic stress elicits regulatory volume decrease (RVD), in which the WNK-SPAK/OSR1 pathway remains inactive and NKCC1 and KCCs are dephosphorylated. This results in NKCC1 inhibition but stimulation of KCCs, which lead to KCC-mediated efflux of K+ and Cl- along with water, and cell volume decrease.

Figure 2.  Illustration of the WNK-SPAK/OSR1-CCCs cascade in nervous and non-nervous system diseases

Mutations of E3 ubiquitin ligase components cullin 3 (CUL3) and kelch-like 3 (KLHL3) were identified to cause Pseudohypoaldosteronism type II (PHAII) with increased WNK1 and WNK4 abundance in kidney. Gene mutations in WNK1 and WNK4 also cause PHAII with compromised cell volume homeostasis. In addition, osmotic stress can trigger WNK-SPAK/OSR1 complex activation, which leads to downstream phosphorylation of CCCs, especially stimulatory phosphorylation of NKCC1 and inhibitory phosphorylation of KCCs. Overstimulation of NKCC1 increases cytotoxic edema, enlarges infarction, and worsens neurobehavioral function in ischemic stroke. Hyperactive NKCC1 increases CSF secretion by the choroid plexus epithelium and causes post-hemorrhagic hydrocephalus after intraventricular hemorrhage. On the other hand, phosphorylation of KCC2 by WNK-SPAK/OSR1 decreases its Cl- efflux and reduces GABA-mediated inhibition of spinal nerve transmission and causes neuropathic pain. To date, no direct evidence links oxidative stress or inflammation to WNK activation in the nervous system. However, oxidative stress can directly activate SPAK/OSR1, which in turn regulates WNK activity, thus indirectly activates WNK; inflammation-induced stimulation of the WNK-SPAK/OSR1 pathway could also increase WNK activity. Dysfunction of KCC3, such as via KCC3 mutation, leads to compromised cell volume homeostasis and causes hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), hearing loss and a reduced threshold for seizure. Hereditary sensory and autonomic neuropathy type II (HSANII) caused by HSN2 gene mutations leads to a loss-of-function for WNK1 activity. Taken together, the WNK-SPAK/OSR1-CCC signaling pathway emerges as a new therapeutic target for nervous and non-nervous system disorders.

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