Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain
Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain
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DOI：
10.1523/jneurosci.5037-07.2008
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发表时间：
2008-02-06
影响因子：
5.3
通讯作者：
Geisslinger, Gerd
中科院分区：
文献类型：
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作者：
Schmidtko, Achim;Gao, Wei;Geisslinger, Gerd
CGMP/cGMP依赖的蛋白激酶I(CGKI)信号通路在脊髓伤害性信息传递中起重要作用。然而，在这方面，cGKI的下游目标迄今尚未确定。通过酵母双杂交筛选，我们分离到了半胱氨酸富含蛋白2(CRP2)，作为一种新型的脊髓cGKI相互作用因子。CRP2在小鼠脊髓I层和II层表达，与cGKI、降钙素基因相关肽和异凝素B4共定位。此外，CRP2mRNA阳性的背根节(DRG)神经元多数表达cGKI和外周蛋白。CRP2以cGMP依赖的方式被磷酸化，其在脊髓和后爪伤害性刺激后的DRG中的表达增加。为了阐明CRP2在伤害性感受中的功能作用，我们分析了靶向缺失CRP2的小鼠。CRP2基因缺陷(CRP2(-/-))小鼠表现出对急性伤害性反应和坐骨神经轴突损伤后的正常行为反应，但在炎症性痛觉过敏模型中与野生型小鼠相比，伤害性行为增加。鞘内注射cGMP类似物可增加野生型小鼠的伤害性行为，但对CRP2(-/-)小鼠无影响，表明CRP2的存在对cGMP介导的伤害性行为具有重要意义。这些数据表明，CRP2是cGKI介导的脊髓伤害性信息处理的一个新的下游效应器，并表明CRP2在炎症性疼痛的产生中具有抑制作用。
The cGMP/cGMP-dependent protein kinase I (cGKI) signaling pathway plays an important role in spinal nociceptive processing. However, downstream targets of cGKI in this context have not been identified to date. Using a yeast two-hybrid screen, we isolated cysteine-rich protein 2 (CRP2) as a novel cGKI interactor in the spinal cord. CRP2 is expressed in laminas I and II of the mouse spinal cord and is colocalized with cGKI, calcitonin gene-related peptide, and isolectin B4. Moreover, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and peripherin. CRP2 is phosphorylated in a cGMP-dependent manner, and its expression increases in the spinal cord and in DRGs after noxious stimulation of a hindpaw. To elucidate the functional role of CRP2 in nociception, we analyzed mice with a targeted deletion of CRP2. CRP2-deficient (CRP2(-/-)) mice demonstrate normal behavioral responses to acute nociception and after axonal injury of the sciatic nerve, but increased nociceptive behavior in models of inflammatory hyperalgesia compared with wild-type mice. Intrathecal administration of cGMP analogs increases the nociceptive behavior in wild-type but not in CRP2(-/-) mice, indicating that the presence of CRP2 is important for cGMP-mediated nociception. These data suggest that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain.