Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

Abstract

WNK1/HSN2 kinase, mutated in a Mendelian form of congenital pain insensitivity, contributes to a maladaptive decrease in KCC2 cotransporter activity and a loss of GABA inhibition in the spared nerve injury (SNI) model of neuropathic pain by increasing KCC2 inhibitory phosphorylation at Thr906/Thr1007. Antagonizing WNK1/HSN2 signaling reduces SNI-induced cold allodynia and mechanical hyperalgesia, decreases up-regulated KCC2 Thr906/Thr1007 phosphorylation, and normalizes pathological GABA depolarizations of injured spinal cord lamina II neurons. These data collectively provide novel mechanistic insight into, and a compelling therapeutic target for, neuropathic pain after nerve injury.

Exercise restores chloride homeostasis and decreases spasticity through the BDNF-KCC2 pathway after chronic SCI

“…WNKs inactivates KCC2 and activates NKCC1, providing a coordinated control over [Cl -]i , Alessi et al, 2014. Decreasing WNK1 activity triggers a hyperpolarizing shift in GABA responses by enhancing KCC2-mediated Cl − extrusion (Friedel et al, 2015) and reduces allodynia and hyperalgesia in SDH neurons (Kahle et al, 2016). The WNK1 pathway can be activated by lower levels of [Cl -]i, a hallmark of SCI.…”

WNK Kinases in Development and Disease

“…Wnk1 mutant mice specifically lacking the HSN2 exon ( Wnk1ΔHsn2 ) have a somewhat different phenotype, with normal peripheral sensory neuron morphology and distribution (Kahle et al, 2016). Nevertheless, these mice were less susceptible to pain hypersensitivity resulting from peripheral nerve injury.…”

“…Nevertheless, these mice were less susceptible to pain hypersensitivity resulting from peripheral nerve injury. Interestingly, in mice, loss of Wnk1ΔHsn2 led to a reduced phosphorylation of KCC2 and thus a more active transporter (Kahle et al, 2016). Thus, the WNK1 HSN2 isoform may be a target for treatment of pain syndromes resulting from peripheral nerve injury.…”

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

“…In mature neurons, KCC2 expression and function is rapidly regulated by neuronal activity via multiple posttranslational mechanisms 4,5 . Thus, Ca 2+ influx through postsynaptic NMDA receptors or during prolonged postsynaptic firing 6 rapidly reduces KCC2 membrane expression and function through protein phosphatase 1-dependent dephosphorylation of its Ser940 residue and protein cleavage by the calcium-activated protease calpain 7,8,9 . Conversely, chloride influx through GABAA receptors stabilizes KCC2 at the plasma membrane via chloride-mediated inhibition of the serine/threonine WNK1 kinase and its downstream effectors SPAK/OSR1, which phosphorylate KCC2 on Thr906 and Thr1007 residues 10,11,12 . Finally, KCC2 expression is also regulated by several neuromodulators acting on G-protein couples receptors 13 as well as neurotrophins such as BDNF acting via TrkB signaling 14 .…”