Journal
SCIENCE SIGNALING
Volume 9, Issue 421, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aad0163
Keywords
-
Categories
Funding
- Canadian Institutes of Health Research [179251]
- Manton Center for Orphan Disease Research at Boston Children's Hospital and Harvard Medical School
- Harvard-MIT Basic Neuroscience Grant
- Reseau de Medecine Genetique appliquee, Claude-Laberge postdoctoral fellowship
- Fonds de la Recherche en Sante du Quebec postdoctoral fellowship
- Canadian Institutes of Health Research
- [RO1DE022912]
Ask authors/readers for more resources
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 Thr(906) and Thr(1007), resulting in an associated loss of GABA (g-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available