Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors.
Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors.
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DOI：
10.1097/j.pain.0000000000001026
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发表时间：
2017-11
期刊：
影响因子：
7.4
通讯作者：
Khanna R
中科院分区：
文献类型：
--
作者：
Moutal A;Wang Y;Yang X;Ji Y;Luo S;Dorame A;Bellampalli SS;Chew LA;Cai S;Dustrude ET;Keener JE;Marty MT;Vanderah TW;Khanna R
1型神经纤维瘤病(NF1)是一种与NF1基因失活突变或纯合子缺失有关的遗传性疾病，以肿瘤发生、认知功能障碍、癫痫发作、偏头痛和疼痛为特征。对人类NF1组织的组学研究证实，崩溃蛋白反应介体蛋白2(CRMP2)的表达增加，CRMP2是一种胞浆蛋白，据报道调节突触前N型电压门控钙通道(Cav2.2)的运输和活性。由于Nf1基因的蛋白产物神经纤维蛋白与CRMP2结合并抑制CRMP2，所以神经纤维蛋白-CRMP2信号通路可能会影响钙通道的活性，调节伤害性神经传递和体内对伤害性刺激的反应。在这里，我们研究了神经纤维素-CRMP2相互作用在Cav2.2上的作用。神经纤维蛋白和CRMP2之间的>；275肽的图谱确定了一种由15个氨基酸组成的CRMP2衍生的多肽，当融合到HIV-1的TAT转导结构域时，它可以抑制背根神经节神经元中的钙内流。该多肽模拟神经纤维蛋白对CRMP2活性的负调节作用。经TAT-CRMP2/神经纤维素调节肽1(t-CNRP1)处理的神经元Cav2.2膜定位减少，神经纤维素-CRMP2和CRMP2-Cav2.2相互作用解偶联。对纳米盘膜蛋白文库的蛋白质组学分析表明，Synaxin 1A是一种新的CRMP2结合蛋白，其与CRMP2的相互作用在神经纤维蛋白缺失的细胞中被增强，而被t-CNRP1抑制。T-CNRP1抑制刺激诱导的腰髓脑片降钙素基因相关肽的释放。在炎症、手术后和神经病理性疼痛的实验模型中，鞘内给药t-CNRP1具有抗伤害性。我们的结果证明了t-CNRP1抑制CRMP2蛋白-蛋白相互作用在潜在的疼痛治疗中的作用。
Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or a homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in the expression of collapsin response mediator protein 2 (CRMP2), a cytosolic protein reported to regulate the trafficking and activity of presynaptic N-type voltage-gated calcium (Cav2.2) channels. Because neurofibromin, the protein product of the Nf1 gene, binds to and inhibits CRMP2, the neurofibromin–CRMP2 signaling cascade will likely affect Ca2+ channel activity and regulate nociceptive neurotransmission and in vivo responses to noxious stimulation. Here, we investigated the function of neurofibromin–CRMP2 interaction on Cav2.2. Mapping of >275 peptides between neurofibromin and CRMP2 identified a 15-amino acid CRMP2–derived peptide that, when fused to the tat transduction domain of HIV-1, inhibited Ca2+ influx in dorsal root ganglion neurons. This peptide mimics the negative regulation of CRMP2 activity by neurofibromin. Neurons treated with tat-CRMP2/neurofibromin regulating peptide 1 (t-CNRP1) exhibited a decreased Cav2.2 membrane localization, and uncoupling of neurofibromin–CRMP2 and CRMP2–Cav2.2 interactions. Proteomic analysis of a nanodisc-solubilized membrane protein library identified syntaxin 1A as a novel CRMP2-binding protein whose interaction with CRMP2 was strengthened in neurofibromin-depleted cells and reduced by t-CNRP1. Stimulus-evoked release of calcitonin gene–related peptide from lumbar spinal cord slices was inhibited by t-CNRP1. Intrathecal administration of t-CNRP1 was antinociceptive in experimental models of inflammatory, postsurgical, and neuropathic pain. Our results demonstrate the utility of t-CNRP1 to inhibit CRMP2 protein–protein interactions for the potential treatment of pain.
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影响因子：
64.5
作者：
CAWTHON, RM;WEISS, R;WHITE, R
通讯作者：
WHITE, R
影响因子：
3.5
作者：
Hussl S;Kubista H;Boehm S
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56.9
作者：
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SCHELLER, RH
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3.5
作者：
Brittain, Joel M.;Wang, Yuying;Khanna, Rajesh
通讯作者：
Khanna, Rajesh
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14.5
作者：
Créange, A;Zeller, J;Wolkenstein, P
通讯作者：
Wolkenstein, P