Format

Send to

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

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

Author information

1
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02124, USA. guy.rouleau@mcgill.ca kristopher.kahle@yale.edu.
2
Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec H3A 2B4, Canada. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada.
3
F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
4
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
5
Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec H3A 2B4, Canada.
6
Department of Psychology and Centre for Research on Pain, McGill University, Montréal, Quebec H3A 0G1, Canada.
7
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
8
Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02124, USA.
9
Institut des Neurosciences Cellulaires et Integratives, UPR 3212 Centre National de la Recherche Scientifique, and Universite de Strasbourg, 5 rue Blaise Pascal, F-67084 Strasbourg, France.
10
Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec H3A 2B4, Canada. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada. guy.rouleau@mcgill.ca kristopher.kahle@yale.edu.

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.

PMID:
27025876
PMCID:
PMC5723157
DOI:
10.1126/scisignal.aad0163
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center