Identification of a receptor for neuropeptide VGF and its role in neuropathic pain.
Identification of a receptor for neuropeptide VGF and its role in neuropathic pain.
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DOI：
10.1074/jbc.m113.510917
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发表时间：
2013-11-29
期刊：
影响因子：
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通讯作者：
Okuse K
中科院分区：
文献类型：
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作者：
Chen YC;Pristerá A;Ayub M;Swanwick RS;Karu K;Hamada Y;Rice AS;Okuse K
背景：VGF是一种参与慢性疼痛的神经肽。结果：VEGF衍生肽TLQP-21激活巨噬细胞。我们鉴定了gC 1 qR作为TLQP-21的受体。结论：TLQP-21和gC 1 qR参与慢性疼痛通路。意义：TLQP-21和gC 1 qR可能是治疗慢性疼痛的药物靶点。VGF（nonacronymic）是一种神经肽前体，在能量平衡、生殖、海马突触可塑性和疼痛的调节中发挥多种作用。来自许多疼痛模型的数据显示，感觉神经元中的VGF显著上调。TLQP-21是一种VEGF衍生的神经肽，当皮下注射到小鼠后爪时，已显示出诱导痛觉过敏反应。然而，VEGF衍生的神经肽在神经性疼痛中的确切作用以及VEGF衍生肽的受体的分子身份还有待研究。在这里，我们确定了gC 1 qR，C1 q受体的球状头部，作为TLQP-21的受体，使用化学交联结合质谱分析。TLQP-21引起大鼠巨噬细胞和小胶质细胞内Ca 2+水平增加。将TLQP-21刺激的巨噬细胞接种到大鼠后爪中引起机械超敏反应。通过siRNA或针对gC 1 qR的中和抗体减弱巨噬细胞中细胞内Ca 2+水平的增加。此外，应用gC 1 qR-中和抗体的大鼠部分坐骨神经结扎导致延迟神经损伤相关的机械性超敏反应。这些结果表明，gC 1 qR是TLQP-21的受体，并通过激活巨噬细胞在慢性疼痛中发挥重要作用。由于TLQP-21和gC 1 qR之间的直接关联是激活巨噬细胞所必需的，并导致超敏反应，因此破坏这种相互作用可能是开发新型镇痛药的一种有用的新方法。
Background: VGF is a neuropeptide involved in chronic pain. Results: VGF-derived peptide TLQP-21 activates macrophages. We identified gC1qR as a receptor for TLQP-21. Conclusion: TLQP-21 and gC1qR are involved in chronic pain pathways. Significance: TLQP-21 and gC1qR may be drug targets for chronic pain treatment. VGF (nonacronymic) is a neuropeptide precursor that plays multiple roles in regulation of energy balance, reproduction, hippocampal synaptic plasticity, and pain. Data from a number of pain models showed significant up-regulation of VGF in sensory neurons. TLQP-21, one of the VGF-derived neuropeptides, has been shown to induce a hyperalgesic response when injected subcutaneously into the hind paw of mice. However, the precise role of VGF-derived neuropeptides in neuropathic pain and the molecular identity of the receptor for VGF-derived peptides are yet to be investigated. Here we identified gC1qR, the globular heads of the C1q receptor, as the receptor for TLQP-21 using chemical cross-linking combined with mass spectrometry analysis. TLQP-21 caused an increase in intracellular Ca2+ levels in rat macrophages and microglia. Inoculation of TLQP-21-stimulated macrophages into rat hind paw caused mechanical hypersensitivity. The increase in intracellular Ca2+ levels in macrophages was attenuated by either siRNA or neutralizing antibodies against gC1qR. Furthermore, application of the gC1qR-neutralizing antibody to rats with partial sciatic nerve ligation resulted in a delayed onset of nerve injury-associated mechanical hypersensitivity. These results indicate that gC1qR is the receptor for TLQP-21 and plays an important role in chronic pain through activation of macrophages. Because direct association between TLQP-21 and gC1qR is required for activation of macrophages and causes hypersensitivity, disrupting this interaction may be a useful new approach to develop novel analgesics.