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“WNK”ing out pain
Mutations in the HSN2 exon present in the nervous system–specific isoform of the kinase WNK1 cause an ulcerating neuropathy disorder called hereditary sensory and autonomic neuropathy type IIA (HSANII). HSANII affects the peripheral and spinal nerves and results in loss of touch, temperature, and pain sensation. Kahle et al. generated transgenic mice specifically lacking this alternatively spliced variant of WNK1, which is present in the spinal cord’s dorsal horn, the gateway for pain processing from the periphery to the brainstem. These mice exhibited no gross neurological defects and did not exhibit symptoms of HSANII, likely because mutations in HSANII patients generate a truncated form of the kinase that has an intact catalytic domain. The HSN2-deficient mice were protected from pain hypersensitivity in a model of neuropathic pain resulting from peripheral nerve injury, but not in an inflammatory pain model. Mechanistically, HSN2-deficient mice had less phosphorylation of the K+-Cl− cotransporter KCC2 in the nerves, which resulted in an increase in KCC2 activity, a decrease in the amount of Cl− in the nerves, and restoration of the inhibitory response to GABA. Thus, by alleviating GABA “disinhibition,” a known major contributor to neuropathic pain, drugs that inhibit HSN2 might reduce injury-induced neuropathic pain.
HSN2 is 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 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+-Cl− cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr906 and Thr1007, 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 Thr906 and Thr1007 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.