Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits.
Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits.
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DOI：
10.1523/jneurosci.5324-09.2010
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发表时间：
2010-02-10
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影响因子：
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通讯作者：
Zylka MJ
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文献类型：
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作者：
Sowa NA;Taylor-Blake B;Zylka MJ
外-5 '-核苷酸酶（NT 5E，CD 73）是一种膜锚定蛋白，在多种组织中将细胞外腺苷5'-单磷酸（AMP）水解为腺苷，但尚未在伤害性神经元中直接研究。我们发现NT 5E位于背根神经节（DRG）的肽能和非肽能伤害性感受神经元以及脊髓第二层（胶状质）的轴突终末上。NT 5E还位于表皮角质形成细胞、真皮细胞和表皮中的伤害性轴突终末上。神经损伤后，NT 5E蛋白和AMP组织化学染色在II层协调减少。此外，在Nt 5e −/−小鼠的DRG神经元和脊髓中，AMP水解活性降低。AMP与腺苷激酶抑制剂5-iodotubericidin联合使用时，在Nt 5e −/−小鼠中的抗伤害效应降低了约50%，在腺苷A1受体（A1 R，Adora 1）敲除小鼠中消除。此外，Nt 5e −/−小鼠在尾部浸泡试验、完全弗氏佐剂（CFA）炎性疼痛模型和备用神经损伤（SNI）神经性疼痛模型中显示出增强的敏感性。总的来说，我们的数据表明，外核苷酸酶NT 5E调节伤害性感受，水解AMP腺苷在伤害性回路，并代表了一个新的分子靶点，用于治疗慢性疼痛。此外，我们的数据表明NT 5E很好地定位于调节皮肤细胞和感觉轴突之间的核苷酸信号传导。
Ecto-5’-nucleotidase (NT5E, CD73) is a membrane-anchored protein that hydrolyzes extracellular adenosine 5’-monophosphate (AMP) to adenosine in diverse tissues but has not been directly studied in nociceptive neurons. We found that NT5E was located on peptidergic and nonpeptidergic nociceptive neurons in dorsal root ganglia (DRG) and on axon terminals in lamina II (the substantia gelatinosa) of spinal cord. NT5E was also located on epidermal keratinocytes, cells of the dermis and on nociceptive axon terminals in the epidermis. Following nerve injury, NT5E protein and AMP histochemical staining were coordinately reduced in lamina II. In addition, AMP hydrolytic activity was reduced in DRG neurons and spinal cord of Nt5e−/− mice. The antinociceptive effects of AMP, when combined with the adenosine kinase inhibitor 5-iodotubericidin, were reduced by ~50% in Nt5e−/− mice and were eliminated in Adenosine A1 receptor (A1R, Adora1) knockout mice. Additionally, Nt5e−/− mice displayed enhanced sensitivity in the tail immersion assay, in the complete Freund's adjuvant (CFA) model of inflammatory pain and in the spared nerve injury (SNI) model of neuropathic pain. Collectively, our data indicate that the ectonucleotidase NT5E regulates nociception by hydrolyzing AMP to adenosine in nociceptive circuits and represents a new molecular target for the treatment of chronic pain. Moreover, our data suggest NT5E is well localized to regulate nucleotide signaling between skin cells and sensory axons.