INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, France.
UMR5203, INSERM U1191, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France.
Sci Rep. 2016 Nov 2;6:36407. doi: 10.1038/srep36407.
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.
鉴定调控感觉神经元亚型兴奋性的分子机制是开发躯体感觉障碍治疗方法的关键要求。在这里，我们表明，Na,K-ATPase 调节剂 Fxyd2 特异性地需要设定 Aδ-纤维低阈值机械感受器和 C-纤维伤害感受器亚群的机械敏感性，这一作用与其在脊髓躯体感觉系统中的受限表达模式一致。我们还利用神经病理性疼痛的 spared nerve injury 模型证实，无论是在 Fxyd2 小鼠中持续缺失 Fxyd2 功能还是在神经病理性大鼠中急性缺失 Fxyd2 功能，都能有效缓解外周神经损伤引起的机械性超敏反应。Fxyd2 调节 Aδ-和 C-纤维机械敏感性的作用可能解释了 Fxyd2 敲低的抗痛觉过敏作用。最后，我们揭示了 FXYD2 在人类背根神经节中的进化上保守的受限表达模式，从而将该分子鉴定为治疗外周神经性疼痛管理的有希望的治疗靶点。
