Mamet Julien, Lazdunski Michel, Voilley Nicolas
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Sophia Antipolis, 06560 Valbonne, France.
J Biol Chem. 2003 Dec 5;278(49):48907-13. doi: 10.1074/jbc.M309468200. Epub 2003 Sep 30.
Nerve growth factor (NGF) is a key element of inflammatory pain. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. Acid-sensing ion channel 3 (ASIC3), a depolarizing sodium channel gated by protons during tissue acidosis, is specifically expressed in sensory neurons. It has been associated to cardiac ischemic and inflammatory pains. We previously showed that low endogenous NGF was responsible for ASIC3 basal expression and high NGF during inflammation increased ASIC3 expression parallely to the development of neuron hyperexcitability associated with hyperalgesia. NGF is known to activate numerous signaling pathways through trkA and p75 receptors. We now show that (i). NGF controls ASIC3 basal expression through constitutive activation of a trkA/phospholipase C/protein kinase C pathway, (ii). high inflammatory-like NGF induces ASIC3 overexpression through a trkA/JNK/p38MAPK pathway and a p75-dependent mechanism as a transcriptional switch, and (iii). NGF acts through AP1 response elements in ASIC3 encoding gene promoter. These new data indicate potential targets that could be used to develop new treatments against inflammatory pain.
神经生长因子（NGF）是炎性疼痛的关键因素。它通过上调编码受体、离子通道和神经肽的基因转录来诱导痛觉过敏。酸敏感离子通道3（ASIC3）是一种在组织酸中毒时由质子门控的去极化钠通道，在感觉神经元中特异性表达。它与心脏缺血性疼痛和炎性疼痛有关。我们之前表明，内源性NGF水平低是ASIC3基础表达的原因，而炎症期间高浓度的NGF会使ASIC3表达增加，这与痛觉过敏相关的神经元过度兴奋的发展平行。已知NGF通过trkA和p75受体激活众多信号通路。我们现在表明：（i）. NGF通过trkA/磷脂酶C/蛋白激酶C途径的组成性激活来控制ASIC3的基础表达；（ii）. 高浓度类似炎症状态的NGF通过trkA/JNK/p38MAPK途径和一种作为转录开关的p75依赖性机制诱导ASIC3过表达；（iii）. NGF通过ASIC3编码基因启动子中的AP1反应元件发挥作用。这些新数据表明了可用于开发抗炎性疼痛新疗法的潜在靶点。
