Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury.
Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury.
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DOI：
10.1186/1744-8069-5-22
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发表时间：
2009-05-02
期刊：
影响因子：
3.3
通讯作者：
Inoue K
中科院分区：
文献类型：
--
作者：
Hasegawa S;Kohro Y;Tsuda M;Inoue K
周围神经损伤导致持续的神经病理性疼痛状态，其中无害的刺激诱发疼痛行为（触觉异常性疼痛），但其潜在机制在很大程度上仍然未知。我们以前已经表明，脊髓神经损伤诱导激活胞浆磷脂酶A2（cPLA 2）在受伤的背根神经节（DRG）神经元，有助于触觉异常性疼痛。然而，关于神经损伤后激活cPLA 2的信号通路知之甚少。在本研究中，我们试图确定在神经病理性疼痛的动物模型中受损DRG神经元中cPLA 2激活的潜在机制，重点是丝裂原活化蛋白激酶（MAPKs）和Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）。药理学抑制p38或细胞外信号调节激酶（ERK）在受伤的DRG，这导致抑制触觉异常性疼痛的发展，并没有影响cPLA 2磷酸化和易位神经损伤后。相比之下，CaMKII抑制剂阻止神经损伤诱导的触觉异常性疼痛的发展和表达，并降低cPLA 2磷酸化水平和显示对神经损伤的cPLA 2易位的DRG神经元的数量。将ATP应用于培养的DRG神经元增加了质膜附近磷酸化cPLA 2和CaMKII的水平，并引起这两种蛋白质的物理关联。此外，ATP刺激的cPLA 2和CaMK Ⅱ磷酸化被抑制的选择性P2 X3 R/P2 X2 +3R拮抗剂和非选择性电压依赖性钙通道（VDCC）阻滞剂。这些结果表明，CaMKII（而不是MAPKs）在周围神经损伤后的cPLA 2激活中发挥重要作用，可能是通过初级传入神经元中的P2 X3 R/P2 X2 + 3 R和VDCC。
Peripheral nerve injury leads to a persistent neuropathic pain state in which innocuous stimulation elicits pain behavior (tactile allodynia), but the underlying mechanisms have remained largely unknown. We have previously shown that spinal nerve injury induces the activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia. However, little is known about the signaling pathway that activates cPLA2 after nerve injury. In the present study, we sought to determine the mechanisms underlying cPLA2 activation in injured DRG neurons in an animal model of neuropathic pain, focusing on mitogen-activated protein kinases (MAPKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Pharmacological inhibition of either p38 or extracellular signal-regulated kinase (ERK) in the injured DRG, which led to suppression of the development of tactile allodynia, did not affect cPLA2 phosphorylation and translocation after nerve injury. By contrast, a CaMKII inhibitor prevented the development and expression of nerve injury-induced tactile allodynia and reduced both the level of cPLA2 phosphorylation and the number of DRG neurons showing translocated cPLA2 in response to nerve injury. Applying ATP to cultured DRG neurons increased the level of both phosphorylated cPLA2 and CaMKII in the vicinity of the plasma membrane and caused physical association of these two proteins. In addition, ATP-stimulated cPLA2 and CaMKII phosphorylation were inhibited by both a selective P2X3R/P2X2+3R antagonist and a nonselective voltage-dependent Ca2+ channel (VDCC) blocker. These results suggest that CaMKII, but not MAPKs, has an important role in cPLA2 activation following peripheral nerve injury, probably through P2X3R/P2X2+3R and VDCCs in primary afferent neurons.
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DOI：
10.1124/jpet.107.132167
发表时间：
2008-04-01
影响因子：
3.5
作者：
Luo, Fang;Yang, Cheng;Wang, Zaijie Jim
通讯作者：
Wang, Zaijie Jim
影响因子：
4.8
作者：
Evans, JH;Spencer, DM;Leslie, CC
通讯作者：
Leslie, CC
影响因子：
7.4
作者：
MINAMI, T;UDA, R;HAYAISHI, O
通讯作者：
HAYAISHI, O
影响因子：
4.8
作者：
Muthalif, MM;Hefner, Y;Malik, KU
通讯作者：
Malik, KU
影响因子：
64.8
作者：
Bayer, KU;De Koninck, P;Schulman, H
通讯作者：
Schulman, H