Research graph
References from Targeting KCC2 and NKCC1 for spinal motor dysfunction: pharmacology, therapeutic opportunities, and translational roadmap. Local targets link to admitted publications; unresolved targets remain external evidence.
Removal of the potassium chloride co-transporter from the somatodendritic membrane of axotomized motoneurons is independent of BDNF/TrkB signaling but is controlled by neuromuscular innervation
10.1523/eneuro.0172-19.2019 · 2019 · External reference
Electromyography of rat soleus, medical gastrocnemius, and tibialis anterior during hind limb suspension
10.1016/0014-4886(87)90225-1 · 1987 · External reference
Intrinsic optical signals in the dorsal horn of rat spinal cord slices elicited by brief repetitive stimulation
10.1046/j.1460-9568.2002.02006.x · 2002 · External reference
Inhibition of KCC2 in mouse spinal cord neurons leads to hypersensitivity to thermal stimulation
10.1213/ane.0b013e31822e0a5d · 2011 · External reference
Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures
10.1016/j.nbd.2016.02.014 · 2016 · External reference
Silencing of Ago-2 interacting protein SERBP1 relieves KCC2 repression by miR-92 in neurons
10.3390/cells11061052 · 2022 · External reference
Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer’s disease and 5XFAD mice
10.1093/brain/awae126 · 2024 · External reference
Selective effects of baclofen on use-dependent modulation of GABAB inhibition after tetraplegia
10.1523/jneurosci.1552-13.2013 · 2013 · External reference
Inhibition of WNK3 Kinase signaling reduces brain damage and accelerates neurological recovery after stroke
10.1161/strokeaha.115.008939 · 2015 · External reference
Hyperreflexia after corticospinal tract lesion reflects 1 A afferent circuit changes not increased KCC2 hyperexcitability
10.1016/j.expneurol.2025.115401 · 2025 · External reference
Rehabilitation decreases spasticity by restoring chloride homeostasis through the brain-derived neurotrophic factor-KCC2 pathway after spinal cord injury
10.1089/neu.2019.6526 · 2020 · External reference
Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice
10.1016/j.neuint.2022.105441 · 2023 · External reference
SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia
10.1111/cns.14654 · 2024 · External reference
NF-kappaB signaling-mediated activation of WNK-SPAK-NKCC1 cascade in worsened stroke outcomes of Ang II-hypertensive mice
10.1161/strokeaha.121.038351 · 2022 · External reference
Exercise-induced plasticity in signaling pathways involved in motor recovery after spinal cord injury
10.3390/ijms22094858 · 2021 · External reference
KCC2 enhancers normalize reflex responses and improve locomotor function after chronic spinal cord injury
10.1113/jp287774 · 2025 · External reference
Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury
10.1016/j.expneurol.2021.113605 · 2021 · External reference
Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2
10.1073/pnas.1213680110 · 2013 · External reference
Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury
10.1038/nm.2107 · 2010 · External reference
Differential effects of spinal cord transection on glycinergic and GABAergic synaptic signaling in sub-lesional lumbar motoneurons
10.1016/j.jchemneu.2020.101847 · 2021 · External reference
VEGF, but Not BDNF, prevents the downregulation of KCC2 induced by axotomy in extraocular motoneurons
10.3390/ijms25189942 · 2024 · External reference
The small molecule CLP257 does not modify activity of the K+–Cl− co-transporter KCC2 but does potentiate GABAA receptor activity
10.1038/nm.4442 · 2017 · External reference
Bumetanide increases postsynaptic inhibition after chronic SCI and decreases presynaptic inhibition with step-training
10.1113/jp283753 · 2023 · External reference
Dose-dependent reversal of KCC2 hypofunction and phenobarbital-resistant neonatal seizures by ANA12
10.1038/s41598-018-30486-7 · 2018 · External reference
KCC2 downregulation facilitates epileptic seizures
10.1038/s41598-017-00196-7 · 2017 · External reference
10.1016/j.ibneur.2022.04.010 · 2022 · Admitted local publication
VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia
2025 · External reference
Global transgenic upregulation of KCC2 confers enhanced diazepam efficacy in treating sustained seizures
10.1111/epi.17097 · 2022 · External reference
KCC2 downregulation after sciatic nerve injury enhances motor function recovery
10.1038/s41598-023-34701-y · 2023 · External reference
Serotonin receptor and KCC2 gene expression in lumbar flexor and extensor motoneurons posttransection with and without passive cycling
10.1152/jn.00550.2014 · 2015 · External reference
Exercise modulates chloride homeostasis after spinal cord injury
10.1523/jneurosci.0678-14.2014 · 2014 · External reference
Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain
10.1038/nature01868 · 2003 · External reference
The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury
10.1186/1744-8069-4-36 · 2008 · External reference
Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing
10.1093/brain/awz105 · 2019 · External reference
Soleus motoneuron excitability after rat hindlimb unloading using histology and a new electrophysiological approach to record a neurographic analogue of the H-reflex
10.1016/j.expneurol.2006.04.021 · 2006 · External reference
KCC2 rs2297201 gene polymorphism might be a predictive genetic marker of febrile seizures
10.1177/17590914221093257 · 2022 · External reference
Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy
2026 · External reference
Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord
10.1002/cne.25395 · 2022 · External reference
WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons
10.1126/scisignal.aaa0354 · 2015 · External reference
Effects of high frequency repetitive transcranial magnetic stimulation on KCC2 expression in rats with spasticity following spinal cord injury
2017 · External reference
Neuronal HDAC3 knockdown promotes propriospinal detour pathway formation and locomotor recovery in a mouse model of spinal cord injury
10.1126/scitranslmed.adp1873 · 2025 · External reference
The Ste20 kinases Ste20-related proline-alanine-rich kinase and oxidative-stress response 1 regulate NKCC1 function in sensory neurons
10.1074/jbc.m900142200 · 2009 · External reference
Hindlimb unloading: rodent analog for microgravity
10.1152/japplphysiol.00997.2015 · 2016 · External reference
Therapeutic potential of 5HT2CR in alleviating spasticity and pain via modulation of motor neurons and interneurons in spinal cord injury
10.1016/j.isci.2025.113489 · 2025 · External reference
Pharmacological inhibition of SPAK-NKCC1 complex attenuates astrogliosis and restores cerebral blood flow in a mouse model of VCID
10.1186/s40478-025-02137-2 · 2025 · External reference
Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy
10.1002/epi.70258 · 2026 · External reference
Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury
10.1111/j.1749-6632.2010.05462.x · 2010 · External reference
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy
10.1016/j.nbd.2011.01.001 · 2011 · External reference
Molecular components of signal amplification in olfactory sensory cilia
10.1073/pnas.0909032107 · 2010 · External reference
KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients
10.1186/s40478-019-0852-x · 2019 · External reference
Temporal and cell-type specific SPAK-NKCC1 disruption following severe TBI in the developing gyrencephalic brain
10.1186/s40478-026-02257-3 · 2026 · External reference
Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus
10.1038/s41593-023-01290-y · 2023 · External reference
A case of Gitelman syndrome with physical retardation
2017 · External reference
Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization
10.1016/j.expneurol.2016.09.005 · 2016 · External reference
Piezo1 dictates K(+) homeostasis through coordinated regulation of the ubiquitin ligase Kelch-like 3 in RBCs and the kidney
2026 · External reference
Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice
10.1016/j.xcrm.2023.100957 · 2023 · External reference
Trifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through alpha7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats
10.1016/j.biopha.2022.114001 · 2023 · External reference
Activation of WNK1 signaling through Piezo1
10.1073/pnas.2513155122 · 2025 · External reference
Kinase-KCC2 coupling: Cl- rheostasis, disease susceptibility, therapeutic target
10.1152/jn.00865.2015 · 2016 · External reference
Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain
10.1001/jamaneurol.2014.21 · 2014 · External reference
Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy
10.15252/embr.201438840 · 2014 · External reference
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition
10.1126/scisignal.aad0163 · 2016 · External reference
Prochlorperazine withdraws the delayed onset tonic activity of unloaded rat soleus muscle: A pilot study
10.3390/life11111161 · 2021 · External reference
Acute TrkB inhibition rescues phenobarbital-resistant seizures in a mouse model of neonatal ischemia
10.1111/ejn.13094 · 2015 · External reference
Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats
10.1016/j.ymthe.2024.01.029 · 2024 · External reference
Scorpion (Hottentotta tamulus) venom pre-exposure delays functional recovery in mice following peripheral nerve injury
10.1371/journal.pone.0330600 · 2025 · External reference
TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice
10.1172/jci.insight.136007 · 2020 · External reference
Furosemide unmasks inhibitory dysfunction after spinal cord injury in humans: Implications for spasticity
10.1089/neu.2017.5560 · 2019 · External reference
Inefficient maturation of disease-linked mutant forms of the KCC2 potassium-chloride cotransporter correlates with predicted pathogenicity
10.1016/j.jbc.2025.108399 · 2025 · External reference
Rare pathogenic variants in WNK3 cause X-linked intellectual disability
10.1016/j.gim.2022.05.009 · 2022 · External reference
Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway
10.1074/jbc.m702664200 · 2007 · External reference
NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents
10.1038/nn.2806 · 2011 · External reference
Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury
10.1016/j.spinee.2013.06.100 · 2014 · External reference
Inhibiting with-no-lysine kinases enhances K+/Cl− cotransporter 2 activity and limits status epilepticus
10.1093/brain/awab343 · 2022 · External reference
Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review
10.1016/j.neuint.2019.04.003 · 2019 · External reference
Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders
10.1038/tp.2017.10 · 2017 · External reference
Inhibition of HMGB1 attenuates spinal cord edema by reducing the expression of Na+-K+-Cl- Cotransporter-1 and Na+/H+ Exchanger-1 in both astrocytes and endothelial cells after spinal cord injury in rats
10.1089/neu.2022.0318 · 2023 · External reference
Body weight-supported treadmill training ameliorates motoneuronal hyperexcitability by increasing GAD-65/67 and KCC2 expression via TrkB signaling in rats with incomplete spinal cord injury
10.1007/s11064-022-03561-9 · 2022 · External reference
Prochlorperazine increases KCC2 function and reduces spasticity after spinal cord injury
10.1089/neu.2017.5152 · 2017 · External reference
LIFU alleviates neuropathic pain by improving the KCC(2) expression and inhibiting the CaMKIV-KCC(2) pathway in the L4-L5 section of the spinal cord
10.1155/2021/6659668 · 2021 · External reference
Chronic electrical stimulation reduces hyperalgesia and associated spinal changes induced by peripheral nerve injury
10.1111/ner.12927 · 2019 · External reference
NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade
10.1097/ccm.0b013e31816590c4 · 2008 · External reference
BDNF modulated KCC2 ubiquitylation in spinal cord dorsal horn of mice
10.1016/j.ejphar.2021.174205 · 2021 · External reference
Transcutaneous spinal cord stimulation at alternating intensities preferentially prevents the development of spasticity after contusion SCI in rat
10.1113/jp287100 · 2025 · External reference
Multi-session transcutaneous spinal cord stimulation prevents chloride homeostasis imbalance and the development of hyperreflexia after spinal cord injury in rat
10.1016/j.expneurol.2024.114754 · 2024 · External reference
Transmitter and ion channel profiles of neurons in the primate abducens and trochlear nuclei
10.1007/s00429-021-02315-7 · 2021 · External reference
Neuronal K(+)-Cl(-) cotransporter KCC2 as a promising drug target for epilepsy treatment
10.1038/s41401-023-01149-9 · 2024 · External reference
Repeated anodal trans-spinal direct current stimulation results in long-term reduction of spasticity in mice with spinal cord injury
10.1113/jp276952 · 2019 · External reference
Platelet-rich plasma modulates neuroinflammation in an iPSC model of sensory neurons and microglia
10.3390/ijms27167127 · 2026 · External reference
Atrogin-1/MAFbx mRNA expression is regulated by histone deacetylase 1 in rat soleus muscle under hindlimb unloading
10.1038/s41598-019-46753-0 · 2019 · External reference
Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury
10.1016/j.pain.2014.05.004 · 2014 · External reference
Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons
10.3389/fncel.2014.00007 · 2014 · External reference
Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures
10.1073/pnas.1810134115 · 2018 · External reference
Essential role of NKCC1 in NGF-induced neurite outgrowth
10.1016/j.bbrc.2007.05.133 · 2007 · External reference
Quercetin stimulates NGF-induced neurite outgrowth in PC12 cells via activation of Na(+)/K(+)/2Cl(-) cotransporter
10.1159/000331723 · 2011 · External reference
Fatigue-induced motor cortex excitability changes in subjects with spinal cord injury
10.1016/j.brainresbull.2013.09.001 · 2013 · External reference
Analgesic effect of bumetanide on neuropathic pain in patients with spinal cord injury
2021 · External reference
Normalizing HDAC2 levels in the spinal cord alleviates thermal and mechanical hyperalgesia after peripheral nerve injury and promotes GAD65 and KCC2 expression
10.3389/fnins.2019.00346 · 2019 · External reference
Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats
10.1111/cns.70045 · 2024 · External reference
Cation-chloride co-transporters in neuronal communication, development and trauma
10.1016/s0166-2236(03)00068-7 · 2003 · External reference
Knocking down of the KCC2 in rat hippocampal neurons increases intracellular chloride concentration and compromises neuronal survival
10.1113/jphysiol.2010.203703 · 2011 · External reference
NKCC1 phosphorylation stimulates neurite growth of injured adult sensory neurons
10.1523/jneurosci.1337-07.2007 · 2007 · External reference
Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology
10.1126/scisignal.aay0300 · 2019 · External reference
Stimulation of cutaneous low threshold mechanoreceptors in mice after intracolonic capsaicin increases spinal c-Fos labeling in an NKCC1-dependent fashion
10.1016/j.jpain.2012.10.003 · 2013 · External reference
Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons
10.1016/j.pain.2010.09.008 · 2010 · External reference
Calpain fosters the hyperexcitability of motoneurons after spinal cord injury and leads to spasticity
10.7554/elife.51404 · 2019 · External reference
A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation
10.1002/embr.201438749 · 2014 · External reference
Target inhibition of SPAK in choroid plexus attenuates T cell infiltration and demyelination in experimental autoimmune encephalomyelitis
10.1186/s12974-025-03407-5 · 2025 · External reference
Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases
10.3389/fphar.2024.1374408 · 2024 · External reference
BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion
10.1083/jcb.200209011 · 2002 · External reference
New drugs on the horizon for cerebral edema: What’s in the clinical development pipeline?
10.1080/13543784.2020.1813715 · 2020 · External reference
Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain
10.1016/j.neuropharm.2017.02.006 · 2017 · External reference
A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures
10.1111/cge.13049 · 2017 · External reference
Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay
10.1038/srep30072 · 2016 · External reference
Activation of 5-HT(2A) receptors restores KCC2 function and reduces neuropathic pain after spinal cord injury
10.1016/j.neuroscience.2017.08.033 · 2018 · External reference
Molecular signaling effects behind the spontaneous soleus muscle activity induced by 7-day rat hindlimb suspension
10.3390/ijms25158316 · 2024 · External reference
A prochlorperazine-induced decrease in autonomous muscle activity during hindlimb unloading is accompanied by preserved slow myosin mRNA expression
10.3390/cimb45070354 · 2023 · External reference
Continuous use during disuse: mechanisms and effects of spontaneous activity of unloaded postural muscle
10.3390/ijms252212462 · 2024 · External reference
The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension
10.1007/s10974-025-09700-3 · 2025 · External reference
Novel gamma-sarcoglycan interactors in murine muscle membranes
10.1186/s13395-021-00285-2 · 2022 · External reference
Contribution of the potassium-chloride co-transporter KCC2 to the modulation of lumbar spinal networks in mice
10.1111/j.1460-9568.2010.07592.x · 2011 · External reference
SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia
10.1212/nxg.0000000000000478 · 2020 · External reference
The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology
10.3389/fphys.2022.1045520 · 2022 · External reference
The overexpression of insulin-like growth factor-1 and neurotrophin-3 promote functional recovery and alleviate spasticity after spinal cord injury
10.3389/fnins.2022.863793 · 2022 · External reference
K(+)-Cl(-) co-transporter 2 (KCC2) - a membrane trafficking perspective
10.1080/09687688.2017.1393566 · 2016 · External reference
Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice
10.1126/scitranslmed.aau0164 · 2019 · External reference
KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome
10.1073/pnas.1524013113 · 2016 · External reference
The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans
10.1523/jneurosci.1989-09.2009 · 2009 · External reference
BDNF induced by treadmill training contributes to the suppression of spasticity and allodynia after spinal cord injury via upregulation of KCC2
10.1177/1545968314562110 · 2015 · External reference
Plantar mechanical stimulation attenuates protein synthesis decline in disused skeletal muscle via modulation of nitric oxide level
10.1038/s41598-021-89362-6 · 2021 · External reference
NOS-dependent effects of plantar mechanical stimulation on mechanical characteristics and cytoskeletal proteins in rat soleus muscle during hindlimb suspension
10.1096/fj.202100783r · 2021 · External reference
Uncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library
2024 · External reference
Importance of chloride homeostasis in the operation of rhythmic motor networks
2011 · External reference
Plasticity of spinal cord locomotor networks and contribution of cation–chloride cotransporters
10.1016/j.brainresrev.2007.09.003 · 2008 · External reference
Coordinated downregulation of KCC2 and GABA(A) receptor contributes to inhibitory dysfunction during seizure induction
10.1016/j.bbrc.2020.08.082 · 2020 · External reference
Role of SPAK-NKCC1 signaling cascade in the choroid plexus blood-CSF barrier damage after stroke
10.1186/s12974-022-02456-4 · 2022 · External reference
Functional recovery induced by KCC2-enabled relay pathways in completely injured spinal cords in adult rats
2025 · External reference
Therapeutic effects of KCC2 chloride transporter activation on detrusor overactivity in mice with spinal cord injury
10.1152/ajprenal.00271.2022 · 2023 · External reference
Small-molecule WNK inhibition regulates cardiovascular and renal function
10.1038/nchembio.2168 · 2016 · External reference
Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
10.1038/s41467-021-26270-3 · 2021 · External reference
KCC2 overexpressed exosomes meditated spinal cord injury recovery in mice
10.1088/1748-605x/ac956b · 2022 · External reference
NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development
10.1523/jneurosci.2864-12.2012 · 2012 · External reference
Preliminary study of analgesic effect of bumetanide on neuropathic pain in patients with spinal cord injury
10.1016/j.jocn.2020.10.010 · 2020 · External reference
AAV9-mediated KCC2 upregulation enhances functional recovery following cervical spinal cord injury
10.1038/s42003-025-08734-0 · 2025 · External reference
Modulation of brain cation-Cl(-) cotransport via the SPAK kinase inhibitor ZT-1a
10.1038/s41467-019-13851-6 · 2020 · External reference
Functionalized nanozyme delivery of a KCC2-activator conjugate for the promotion of functional recovery after acute spinal cord injury
10.1016/j.mtbio.2025.102624 · 2025 · External reference
Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke
10.1177/0271678x16631561 · 2017 · External reference
Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion
10.1002/brb3.2464 · 2022 · External reference