K-Cl cotransporters, cell volume homeostasis, and neurological disease

doi:10.1016/j.molmed.2015.05.008

Trends in Molecular Medicine

Volume 21, Issue 8, August 2015, Pages 513-523

https://doi.org/10.1016/j.molmed.2015.05.008 Get rights and content

Highlights

•
KCCs have roles in the nervous system beyond modulating GABAergic signaling.
•
KCCs regulate nervous system cell volume, and are mutated in neurological disease.
•
WNK-SPAK kinases modulate volume-sensitive KCC activity.
•
Antagonizing WNK-SPAK-mediated KCC phosphorylation may hold therapeutic promise.

K⁺-Cl^– cotransporters (KCCs) were originally characterized as regulators of red blood cell (RBC) volume. Since then, four distinct KCCs have been cloned, and their importance for volume regulation has been demonstrated in other cell types. Genetic models of certain KCCs, such as KCC3, and their inhibitory WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK) serine-threonine kinases, have demonstrated the evolutionary necessity of these molecules for nervous system cell volume regulation, structure, and function, and their involvement in neurological disease. The recent characterization of a swelling-activated dephosphorylation mechanism that potently stimulates the KCCs has pinpointed a potentially druggable switch of KCC activity. An improved understanding of WNK/SPAK-mediated KCC cell volume regulation in the nervous system might reveal novel avenues for the treatment of multiple neurological diseases.

Section snippets

Cation-Cl^– cotransporters in the brain: beyond NKCC1 and KCC2

Cation-chloride cotransporters (CCCs) are among the most medically relevant ion transporters in the human genome. Multiple members of this family [1], and their upstream regulators [i.e., the Kelch-like family member 3 (KLHL3)/Cullin 3 (CUL3)-WNK-SPAK/Oxidative stress response 1 (OSR1) kinase signaling pathway [2]], are mutated in human Mendelian disorders featuring brain or renal phenotypes resulting from impaired ion homeostasis. CCCs are also targets of several commonly used drugs utilized

Cell volume regulation in the nervous system

Defense against significant changes in cell volume is required for cell function and survival [33]. Cell volume perturbations can result from changes in intracellular osmolarity (isosmotic volume stress) or extracellular osmotic pressure (anisosmotic volume stress). Isosmotic cell swelling, as occurs in cellular energetic failures such as ischemic stroke, results in increases in the intracellular concentration of Na⁺ ([Na⁺]_i) and [Cl^–]_i. Anisosmotic cell swelling, as seen in acute hyponatremia

Swelling-sensitive KCCs in the nervous system

The structure, function, and regulation of the KCCs are highly conserved across evolution, consistent with their essential role in physiology [24]. Since human KCC1 was first cloned in 1996, four human genes encoding human KCCs (hKCC1–4) have been identified, which all have mouse and rat orthologs 19, 25, 44, 45, 46, 47, 48. hKCCs share a similar membrane topology, including hydrophilic N- and C-terminal intracellular domains harboring multiple phosphoresidues important for transporter

KCC3 is essential for nervous system cell volume regulation

Evidence that KCCs are important for cell volume maintenance in the nervous system has been derived from genetically modified worms and flies 47, 54, transgenic or knockout mouse models [31], and human patients with inherited disease-causing mutations 28, 31. Delpire and colleagues first disrupted the KCC3-encoding Slc12a6 gene using homologous recombination in mice [31]. Slc12a6^–/– but not Slc12a6^–/+ mice exhibited weakness and incoordination of rear limbs by 2 weeks of age, correlating with

KCC3 is required for normal structure and function of the human nervous system

Molecular genetics has also established the necessity of KCC3-mediated cell volume regulation in humans. Loss-of-function mutations in KCC3 have been identified as the cause of agenesis of the corpus callosum associated with peripheral neuropathy [ACCPN or hereditary motor and sensory neuropathy/absent corpus collosum (HSMN/ACC)], a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features, and complete or partial agenesis of the corpus callosum [66]. ACCPN is

The Cl^–-sensitive WNK-SPAK kinase complex: master regulator of KCC and N[K]CC volume sensitivity

Until recently, the mechanisms regulating KCC swelling sensitivity were not defined on the molecular level. While cell swelling is a quasi-immediate phenomenon due to the water permeability of a cell membrane, there is a significant time delay in the activation of K⁺-Cl^– cotransport [20]. This delay is temperature dependent, indicating that swelling activation is an energy and/or metabolic-dependent process. In fact, based on kinetic arguments and the use of phosphatase inhibitors, early

Modulation of KCC3 swell activation mechanisms to counter pathological brain swelling

Blocking KCC3 Thr991/Thr1048 inhibitory phosphorylation is a potent mechanism of stimulating KCC activity. Could this mechanism be pharmacologically exploited to protect against isosmotic cell swelling in certain disease states, such as cerebral edema associated with ischemic stroke, epilepsy, or tumors? Interestingly, the sequence context of the KCC phosphorylation site 1 is also conserved in the amino terminus of NKCC1, suggesting a coordinated but opposite regulation of NKCCs and KCCs by a

Exploiting KCC swell activation mechanisms for neurological diseases not associated with cell swelling

Might it also be possible to exploit the biochemical mechanisms of NKCC1 and KCC2 swelling regulation for therapeutic benefit in neurological diseases not associated with cell swelling? Multiple diseases, including seizures, neuropathic pain, autism, schizophrenia, spasticity, and others, feature more depolarized values of E_GABA, and hyperexcitability of GABAergic neurons and circuits, due to pathologically elevated neuronal [Cl^–]_i resulting from increases in NKCC1 activity, or decreases in

Concluding remarks

In neuroscience, considerable attention has been rightly paid to KCC2, which mediates Cl^– efflux in isotonic conditions and is required for the establishment of GABAergic hyperpolarizing synaptic inhibition. However, genetic models of KCC3 and KCC4, and their upstream inhibitory WNK-SPAK kinases, have demonstrated the necessity of swelling-regulated K-Cl cotransport for nervous system development and cell volume regulation, and their involvement in neurological disease. The recent discovery and

References (108)

J.P. Arroyo
The SLC12 family of electroneutral cation-coupled chloride cotransporters
Mol. Aspects Med.
(2013)
A. Mercado
A C-terminal domain in KCC2 confers constitutive K⁺-Cl-cotransport
J. Biol. Chem.
(2006)
P.K. Lauf et al.
A chloride dependent K⁺ flux induced by N-ethylmaleimide in genetically low K⁺ sheep and goat erythrocytes
Biochem. Biophys. Res. Commun.
(1980)
L. Song
Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter
Brain Res. Mol. Brain Res.
(2002)
D.B. Mount
Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family
J. Biol. Chem.
(1999)
M.M. Pearson
Localization of the K(⁺)-Cl(⁻) cotransporter, KCC3, in the central and peripheral nervous systems: expression in the choroid plexus, large neurons and white matter tracts
Neuroscience
(2001)
M.F. Karadsheh
Localization of the KCC4 potassium-chloride cotransporter in the nervous system
Neuroscience
(2004)
N. Byun et al.
Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice
Neurobiol. Dis.
(2007)
J.M. Simard
Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications
Lancet Neurol.
(2007)
Z. Qiu
SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel
Cell
(2014)

C.M. Gillen

Molecular cloning and functional expression of the K-Cl cotransporter from rabbit, rat, and human. A new member of the cation-chloride cotransporter family

J. Biol. Chem.

(1996)

K. Hiki

Cloning, characterization, and chromosomal location of a novel human K⁺-Cl⁻ cotransporter

J. Biol. Chem.

(1999)

C.M. Pellegrino

Molecular identification and expression of erythroid K:Cl cotransporter in human and mouse erythroleukemic cells

Blood Cells Mol. Dis.

(1998)

A. Mercado

Functional comparison of the K⁺-Cl⁻ cotransporters KCC1 and KCC4

J. Biol. Chem.

(2000)

Y. Jiao

A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice

Genomics

(2008)

S. Casula

A dominant negative mutant of the KCC1 K-Cl cotransporter both N-and C-terminal cytoplasmic domains are required for K-Cl cotransport activity

J. Biol. Chem.

(2001)

C.F. Simard

Homooligomeric and heterooligomeric associations between K⁺-Cl⁻ cotransporter isoforms and between K⁺-Cl⁻ and Na⁺-K⁺-Cl⁻ cotransporters

J. Biol. Chem.

(2007)

T. Olsson

Cell swelling, seizures and spreading depression: an impedance study

Neuroscience

(2006)

M. Isokawa

N-methyl-d-aspartic acid-induced and Ca-dependent neuronal swelling and its retardation by brain-derived neurotrophic factor in the epileptic hippocampus

Neuroscience

(2005)

J. Ding et al.

Deletion of KCC3 in parvalbumin neurons leads to locomotor deficit in a conditional mouse model of peripheral neuropathy associated with agenesis of the corpus callosum

Behav. Brain Res.

(2014)

M. Shekarabi

Cellular expression of the K⁺–Cl⁻ cotransporter KCC3 in the central nervous system of mouse

Brain Res.

(2011)

P.K. Lauf

K-Cl co-transport: immunocytochemical and functional evidence for more than one KCC isoform in high K and low K sheep erythrocytes

Comp. Biochem. Physiol. A: Mol. Integr. Physiol.

(2001)

J. Rinehart

Sites of regulated phosphorylation that control K-Cl cotransporter activity

Cell

(2009)

A. Salin-Cantegrel

Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum

J. Biol. Chem.

(2011)

K. Piechotta

Cation chloride cotransporters interact with the stress-related kinases ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1)

J. Biol. Chem.

(2002)

K. Piechotta

Characterization of the interaction of the stress kinase SPAK with the Na⁺-K⁺-2Cl⁻ cotransporter in the nervous system: evidence for a scaffolding role of the kinase

J. Biol. Chem.

(2003)

J.A. Payne

Molecular characterization of a putative K-Cl cotransporter in rat brain: a neuronal-specific isoform

J. Biol. Chem.

(1996)

S.D. Shields

Anatomical and functional analysis of aquaporin 1, a water channel in primary afferent neurons

Pain

(2007)

K.B. Gagnon et al.

Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts

Am. J. Physiol.

(2013)

D.R. Alessi

The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters

Sci. Signal.

(2014)

N. Markadieu et al.

Physiology and pathophysiology of SLC12A1/2 transporters

Pflugers Arch.

(2014)

G. Gamba

Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters

Physiol. Rev.

(2005)

K. Kaila

Cation-chloride cotransporters in neuronal development, plasticity and disease

Nat. Rev. Neurosci.

(2014)

K.T. Kahle

Roles of the cation-chloride cotransporters in neurological disease

Nat. Clin. Pract. Neurol.

(2008)

J.A. Payne

Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K⁺]oregulation

Am. J. Physiol.

(1997)

G. Cellot et al.

GABAergic signaling as therapeutic target for autism spectrum disorders

Front. Pediatrics

(2014)

D. Arion et al.

Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia

Arch. Gen. Psychiatry

(2011)

J. Tornberg

Behavioural phenotypes of hypomorphic KCC2-deficient mice

Eur. J. Neurosci.

(2005)

A. Khanna

Limitations of current GABA agonists in neonatal seizures: towards GABA modulation via the targeting of neuronal Cl-transport

Front. Neurol.

(2013)

P. Boulenguez

Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury

Nat. Med.

(2010)

V. Rangroo Thrane

Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering

Nat. Med.

(2013)

J.A. Coull

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Nature

(2005)

K.T. Kahle

Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter kcc2-mediated chloride extrusion in peripheral neuropathic pain

JAMA Neurol.

(2014)

M.L. Jennings et al.

Kinetics of activation and inactivation of swelling-stimulated K⁺/Cl⁻ transport. The volume-sensitive parameter is the rate constant for inactivation

J. Gen. Physiol.

(1990)

M.L. Jennings et al.

Okadaic acid inhibition of KCl cotransport. Evidence that protein dephosphorylation is necessary for activation of transport by either cell swelling or N-ethylmaleimide

J. Gen. Physiol.

(1991)

P. de los Heros

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K⁺-Cl⁻ co-transporters

Biochem. J.

(2014)

P.K. Lauf et al.

Properties and membrane transport mechanisms of erythrocytes

N.C. Adragna

Regulation of K-Cl cotransport: from function to genes

J. Membr. Biol.

(2004)

T. Boettger

Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold

EMBO J.

(2003)

T. Boettger

Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4

Nature

(2002)

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Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing
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Glia interact with multiple neurons, but it is unclear whether their interactions with each neuron are different. Our interrogation at single-cell resolution reveals that a single glial cell exhibits specificity in its interactions with different contacting neurons. Briefly, C. elegans amphid sheath (AMsh) glia apical-like domains contact 12 neuron-endings. At these ad-neuronal membranes, AMsh glia localize the K/Cl transporter KCC-3 to a microdomain exclusively around the thermosensory AFD neuron to regulate its properties. Glial KCC-3 is transported to ad-neuronal regions, where distal cilia of non-AFD glia-associated chemosensory neurons constrain it to a microdomain at AFD-contacting glial membranes. Aberrant KCC-3 localization impacts both thermosensory (AFD) and chemosensory (non-AFD) neuron properties. Thus, neurons can interact non-synaptically through a shared glial cell by regulating microdomain localization of its cues. As AMsh and glia across species compartmentalize multiple cues like KCC-3, we posit that this may be a broadly conserved glial mechanism that modulates information processing across multimodal circuits.
Cl<sup>−</sup> induces endothelium-dependent mesenteric arteriolar vasorelaxation through the NKCC1/TRPV4/NCX axis
2023, Life Sciences
Although absorbed NaCl increases intestinal blood flow to facilitate absorption and transportation, it is unclear if it can directly mediate mesenteric arterial relaxation. We aimed to investigate and test our hypothesis that Cl⁻ induces mesenteric arterial vasorelaxation via endothelium-dependent hyperpolarization (EDH).
We used wire myograph to study NaCl-induced vasorelaxation of mesenteric arteries isolated from mice. Cl⁻, Ca²⁺ and K⁺ imaging was performed in human vascular endothelial cells pre-treated with pharmacological agents.
The Cl⁻ concentration-dependently induced vasorelaxation of mesenteric arteries likely through EDH. The Cl⁻-induced vasorelaxation was attenuated in TRPV4 KO mice and inhibited by selective blockers of Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) (bumetanide, 10 μM), transient receptor potential vanilloid 4 (TRPV4) (RN-1734, 40 μM), and small conductance Ca²⁺-activated K⁺ channels (SK_Ca) (apamin, 3 μM)/ intermediate conductance Ca²⁺-activated K⁺ channels (IK_Ca) (TRAM-34, 10 μM) and myoendothelial gap junction (18α-glycyrrhetinic acid, 10 μM), but enhanced by a selective activator of IK_Ca/SK_Ca (SKA-31, 0.3 μM). Cl⁻ decreased intracellular K⁺ concentrations in endothelial cells, which was reversed by apamin (200 nM) plus TRAM-34 (500 nM). Extracellular Cl⁻ raised intracellular Cl⁻ concentrations in endothelial cells, which was attenuated by bumetanide (10 μM). Finally, Cl⁻ induced a transient Ca²⁺ signaling via TRPV4 in endothelial cells, which became sustained when the Ca²⁺ exit mode of Na⁺-Ca²⁺ exchanger (NCX) was blocked.
Cl⁻ induces a pure EDH-mediated vasorelaxation of mesenteric arteries through activation of endothelial NKCC1/TRPV4/NCX axis. We have provided a novel insight into the role of Cl⁻-induced vasorelaxation via EDH mechanism.
Acceleration of GABA-switch after early life stress changes mouse prefrontal glutamatergic transmission
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Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called “GABA-switch”.
Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15–P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABA_A receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.
Role of NKCC1 and KCC2 during hypoxia-induced neuronal swelling in the neonatal neocortex
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Neonatal hypoxia causes cytotoxic neuronal swelling by the entry of ions and water. Multiple water pathways have been implicated in neurons because these cells lack water channels, and their membrane has a low water permeability. NKCC1 and KCC2 are cation-chloride cotransporters (CCCs) involved in water movement in various cell types. However, the role of CCCs in water movement in neonatal neurons during hypoxia is unknown. We studied the effects of modulating CCCs pharmacologically on neuronal swelling in the neocortex (layer IV/V) of neonatal mice (post-natal day 8–13) during prolonged and brief hypoxia. We used acute brain slices from Clomeleon mice which express a ratiometric fluorophore sensitive to Cl⁻ and exposed them to oxygen-glucose deprivation (OGD) while imaging neuronal size and [Cl⁻]_i by multiphoton microscopy. Neurons were identified using a convolutional neural network algorithm, and changes in the somatic area and [Cl⁻]_i were evaluated using a linear mixed model for repeated measures. We found that (1) neuronal swelling and Cl⁻ accumulation began after OGD, worsened during 20 min of OGD, or returned to baseline during reoxygenation if the exposure to OGD was brief (10 min). (2) Neuronal swelling did not occur when the extracellular Cl⁻ concentration was low. (3) Enhancing KCC2 activity did not alter OGD-induced neuronal swelling but prevented Cl⁻ accumulation; (4) blocking KCC2 led to an increase in Cl⁻ accumulation during prolonged OGD and aggravated neuronal swelling during reoxygenation; (5) blocking NKCC1 reduced neuronal swelling during early but not prolonged OGD and aggravated Cl⁻ accumulation during prolonged OGD; and (6) treatment with the “broad” CCC blocker furosemide reduced both swelling and Cl⁻ accumulation during prolonged and brief OGD, whereas simultaneous NKCC1 and KCC2 inhibition using specific pharmacological blockers aggravated neuronal swelling during prolonged OGD. We conclude that CCCs, and other non-CCCs, contribute to water movement in neocortical neurons during OGD in the neonatal period.
Glial regulators of ions and solutes required for specific chemosensory functions in Caenorhabditis elegans
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Glia and accessory cells regulate the microenvironment around neurons and primary sensory cells. However, the impact of specific glial regulators of ions and solutes on functionally diverse primary cells is poorly understood. Here, we systemically investigate the requirement of ion channels and transporters enriched in Caenorhabditis elegans Amsh glia for the function of chemosensory neurons. Although Amsh glia ablated worms show reduced function of ASH, AWC, AWA, and ASE neurons, we show that the loss of glial enriched ion channels and transporters impacts these neurons differently, with nociceptor ASH being the most affected. Furthermore, our analysis underscores the importance of K⁺, Cl⁻, and nucleoside homeostasis in the Amphid sensory organ and uncovers the contribution of glial genes implicated in neurological disorders. Our findings build a unique fingerprint of each glial enriched ion channel and transporter and may provide insights into the function of supporting cells of mammalian sensory organs.
KCC2 drives chloride microdomain formation in dendritic blebbing
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Intracellular chloride ion concentration ([Cl^–]_i) homeostasis is critical for excitatory/inhibitory balance and volume regulation in neurons. We quantitatively map spatiotemporal dendritic [Cl^–]_i dynamics during N-methyl-d-aspartate (NMDA) excitotoxicity to determine how Cl^– changes contribute to localized dendritic swelling (blebbing) in stroke-like conditions. Whole-cell patch clamp electrophysiology combined with simultaneous fluorescence lifetime imaging (FLIM) of the Cl^– dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE; MQAE-FLIM) reliably report resting and dynamic [Cl^–]_i shifts in dendrites. NMDA application generates spatially restricted and persistent high [Cl^–]_i subdomains at dendritic blebs in a process that requires Ca²⁺ influx and the subsequent opening of small-conductance Ca²⁺-activated K⁺ (SK) channels. We propose sustained and localized K⁺ efflux increased extracellular K⁺ concentrations ([K⁺]_o) sufficiently at discrete regions to reverse K⁺-Cl^– cotransporter (KCC2) transport and trigger synaptic swelling. Together, our data establish a mechanism for KCC2 to generate pathological [Cl^–]_i microdomains in blebbing with relevance for multiple neurological disorders.

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Trends in Molecular Medicine

ReviewK-Cl cotransporters, cell volume homeostasis, and neurological disease

Highlights

Section snippets

Cation-Cl– cotransporters in the brain: beyond NKCC1 and KCC2

Cell volume regulation in the nervous system

Swelling-sensitive KCCs in the nervous system

KCC3 is essential for nervous system cell volume regulation

KCC3 is required for normal structure and function of the human nervous system

The Cl–-sensitive WNK-SPAK kinase complex: master regulator of KCC and N[K]CC volume sensitivity

Modulation of KCC3 swell activation mechanisms to counter pathological brain swelling

Exploiting KCC swell activation mechanisms for neurological diseases not associated with cell swelling

Concluding remarks

Mol. Aspects Med.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

Neuroscience

Neuroscience

Neurobiol. Dis.

Lancet Neurol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Blood Cells Mol. Dis.

J. Biol. Chem.

Genomics

J. Biol. Chem.

J. Biol. Chem.

Neuroscience

Neuroscience

Behav. Brain Res.

Brain Res.

Comp. Biochem. Physiol. A: Mol. Integr. Physiol.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Pain

Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts

Am. J. Physiol.

The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters

Sci. Signal.

Physiology and pathophysiology of SLC12A1/2 transporters

Pflugers Arch.

Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters

Physiol. Rev.

Cation-chloride cotransporters in neuronal development, plasticity and disease

Nat. Rev. Neurosci.

Roles of the cation-chloride cotransporters in neurological disease

Nat. Clin. Pract. Neurol.

Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K+]oregulation

Am. J. Physiol.

GABAergic signaling as therapeutic target for autism spectrum disorders

Front. Pediatrics

Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia

Arch. Gen. Psychiatry

Behavioural phenotypes of hypomorphic KCC2-deficient mice

Eur. J. Neurosci.

Limitations of current GABA agonists in neonatal seizures: towards GABA modulation via the targeting of neuronal Cl-transport

Front. Neurol.

Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury

Nat. Med.

Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering

Nat. Med.

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Nature

Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter kcc2-mediated chloride extrusion in peripheral neuropathic pain

JAMA Neurol.

Kinetics of activation and inactivation of swelling-stimulated K+/Cl− transport. The volume-sensitive parameter is the rate constant for inactivation

J. Gen. Physiol.

Okadaic acid inhibition of KCl cotransport. Evidence that protein dephosphorylation is necessary for activation of transport by either cell swelling or N-ethylmaleimide

J. Gen. Physiol.

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl− co-transporters

Biochem. J.

Properties and membrane transport mechanisms of erythrocytes

Regulation of K-Cl cotransport: from function to genes

J. Membr. Biol.

Review
K-Cl cotransporters, cell volume homeostasis, and neurological disease

Cation-Cl^– cotransporters in the brain: beyond NKCC1 and KCC2

The Cl^–-sensitive WNK-SPAK kinase complex: master regulator of KCC and N[K]CC volume sensitivity

Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K⁺]oregulation

Kinetics of activation and inactivation of swelling-stimulated K⁺/Cl⁻ transport. The volume-sensitive parameter is the rate constant for inactivation

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K⁺-Cl⁻ co-transporters