ArticleScience signaling2016
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.
Article in Science signaling, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 50 citations in OpenAlex.
- S100A8/S100A9 released by CD11bExperimental & molecular medicine · 2026Article
- A New Phase for WNK Kinase Signaling Complexes as Biomolecular Condensates.Physiology (Bethesda, Md.) · 2024Review
- Inhibition of WNK Kinases in NK Cells Disrupts Cellular Osmoregulation and Control of Tumor Metastasis.Journal of innate immunity · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- Article
- Optogenetic and Chemogenic Control of Pain Signaling: Molecular Markers.International journal of molecular sciences · 2023Review
- WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway.Scientific reports · 2022Article
- An update regarding the role of WNK kinases in cancer.Cell death & disease · 2022Review
- Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression ofFrontiers in molecular neuroscience · 2022Review
- Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.Aging and disease · 2021Review
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
- Clinical Efficacy of Controlled-Release Morphine Tablets Combined with Celecoxib in Pain Management and the Effects on WNK1 Expression.Clinics (Sao Paulo, Brazil) · 2021Article
- Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability.Expert opinion on therapeutic targets · 2020Review
- Microarray analyses of the dorsal root ganglia support a role for innate neuro-immune pathways in persistent pain in experimental osteoarthritis.Osteoarthritis and cartilage · 2020Article
- Reviewing the case for compromised spinal inhibition in neuropathic pain.Journal of neural transmission (Vienna, Austria : 1996) · 2020Review
- Rehabilitation Decreases Spasticity by Restoring Chloride Homeostasis through the Brain-Derived Neurotrophic Factor-KCC2 Pathway after Spinal Cord Injury.Journal of neurotrauma · 2020Article
- Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters.Frontiers in physiology · 2020Review
- Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.Science signaling · 2019Article
- The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases.Aging and disease · 2019Review
- Identification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation.Frontiers in cellular neuroscience · 2019Article
Corrections and comments
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Authors and funding
22 authors at 5 institutions in 3 countries.
Funding
Abstract
HSN2is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking theHsn2exon ofWnk1 Although these mice had normal spinal neuron and peripheral sensory neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K(+)-Cl(-)cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr(906)and Thr(1007), resulting in an associated loss of GABA (γ-aminobutyric acid)-mediated inhibition of spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl(-)such that GABA signaling resulted in a less hyperpolarized state (increased neuronal activity) rather than a more hyperpolarized state (decreased neuronal activity) in mouse spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr(906)and Thr(1007)phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.