Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.
Kahle, KT; Schmouth, J-F; Lavastre, V; et al.Latremoliere, A; Zhang, J; Andrews, N; Omura, T; Laganière, J; Rochefort, D; Hince, P; Castonguay, G; Gaudet, R; Mapplebeck, JCS; Sotocinal, SG; Duan, J; Ward, C; Khanna, AR; Mogil, JS; Dion, PA; Woolf, CJ; Inquimbert, P; Rouleau, GA
Date: 29 March 2016
American Association for the Advancement of Science
HSN2 is a nervous system-predominant exon of of the WNK1 kinase (HSN2-containing splice variant referred to as “WNK1/HSN2”) and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. We created a knockout mouse specifically lacking the HSN2 exon of WNK1. Although these mice had normal spinal neuron and ...
HSN2 is a nervous system-predominant exon of of the WNK1 kinase (HSN2-containing splice variant referred to as “WNK1/HSN2”) and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. We created a knockout mouse specifically lacking the HSN2 exon of WNK1. 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+-Clcotransporter KCC2 by increasing its inhibitory phosphorylation at Thr906 and Thr1007, resulting in an associated loss of GABA-mediated inhibition of spinal paintransmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Clsuch that GABA signaling resulted in depolarization (increased neuronal activity) rather than hyperpolarization (decreased neuronal activity) in mouse spinal nerves. Consistent with the results in the WNK1/HSN2-deficient mice, pharmacologically antagonizing WNK1/HSN2 normalized pathological GABA depolarization of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for, neuropathic pain after nerve injury.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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