Research ArticlePain

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

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Science Signaling  29 Mar 2016:
Vol. 9, Issue 421, pp. ra32
DOI: 10.1126/scisignal.aad0163

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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.

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