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

Sci Signal. 2016 Mar 29;9(421):ra32. doi: 10.1126/scisignal.aad0163.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Exons
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism*
  • Hyperalgesia / physiopathology
  • Hyperalgesia / prevention & control
  • Mice
  • Mice, Transgenic
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Neuralgia / genetics
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Neuralgia / prevention & control
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / metabolism
  • Peripheral Nerve Injuries / physiopathology
  • Peripheral Nerve Injuries / prevention & control
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Spinal Nerves / metabolism*
  • Spinal Nerves / pathology
  • Symporters / genetics
  • Symporters / metabolism
  • Synaptic Transmission*
  • WNK Lysine-Deficient Protein Kinase 1
  • gamma-Aminobutyric Acid / genetics
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Minor Histocompatibility Antigens
  • Symporters
  • potassium-chloride symporters
  • gamma-Aminobutyric Acid
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse