Fxyd2 regulates Aδ- and C-fiber mechanosensitivity and is required for the maintenance of neuropathic pain.
Identification of the molecular mechanisms governing sensory neuron subtype excitability is a key requisite for the development of treatments for somatic sensory disorders. Here, we show that the Na,K-ATPase modulator Fxyd2 is specifically required for setting the mechanosensitivity of Aδ-fiber low-threshold mechanoreceptors and sub-populations of C-fiber nociceptors, a role consistent with its restricted expression profile in the spinal somatosensory system. We also establish using the spared nerve injury model of neuropathic pain, that loss of Fxyd2 function, either constitutively in Fxyd2-/-mice or acutely in neuropathic rats, efficiently alleviates mechanical hypersensitivity induced by peripheral nerve lesions. The role of Fxyd2 in modulating Aδ- and C-fibers mechanosensitivity likely accounts for the anti-allodynic effect of Fxyd2 knockdown. Finally, we uncover the evolutionarily conserved restricted expression pattern of FXYD2 in human dorsal root ganglia, thus identifying this molecule as a potentially promising therapeutic target for peripheral neuropathic pain management.
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
Stéphanie
S
Ventéo
UMR5203, INSERM U1191, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France.|Université de Montpellier, Place Eugène Bataillon, 34090 Montpellier, France.
Sophie
S
Laffray
Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, D-13125 Berlin, Germany.
Christiane
C
Wetzel
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.|Université de Montpellier, Place Eugène Bataillon, 34090 Montpellier, France.
Cyril
C
Rivat
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
Frédérique
F
Scamps
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.|Université de Montpellier, Place Eugène Bataillon, 34090 Montpellier, France.
Ilana
I
Méchaly
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.|Département de Neurochirurgie, Hôpital Gui de Chauliac, CHU, 80 avenue Augustin Fliche, 34295 Montpellier, France.
Luc
L
Bauchet
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
Cédric
C
Raoul
UMR5203, INSERM U1191, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France.
Emmanuel
E
Bourinet
Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, D-13125 Berlin, Germany.
Gary R
GR
Lewin
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
Patrick
P
Carroll
INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
Alexandre
A
Pattyn
D000818:Animals; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D008124:Locomotion; D008297:Male; D008465:Mechanoreceptors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009412:Nerve Fibers / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology*; D009619:Nociceptors / Q000378:metabolism; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; C498816:Fxyd2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase