Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways
Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways
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DOI：
10.3390/ijms20133271
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Uezono, Yasuhito
中科院分区：
文献类型：
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作者：
Miyano, Kanako;Shiraishi, Seiji;Uezono, Yasuhito
卡铂是一种抗癌药物，经常引起化疗引起的周围神经病变（PN）。瞬时受体电位锚蛋白 1 (TRPA1) 是一种非选择性阳离子通道，是一种在感觉神经元中表达的多模式伤害感受器。 TRPA1 不仅参与疼痛传递，还参与异常性疼痛或痛觉过敏的发生。然而，TRPA1 对卡铂诱导的 PN 的影响尚不清楚。我们发现卡铂会诱发机械性异常性疼痛和冷痛觉过敏，并且在卡铂诱发的 PN 模型中观察到的疼痛被 TRPA1 拮抗剂 HC-030031 显着抑制，而 TRPA1 蛋白水平没有变化。在表达人 TRPA 的细胞中，卡铂对细胞内 Ca2+ 浓度 ([Ca2+](i)) 的变化没有影响；然而，卡铂预处理增强了 TRPA1 激动剂异硫氰酸烯丙酯 (AITC) 诱导的 [Ca2+](i) 增加。这些作用可被蛋白激酶 A (PKA) 抑制剂抑制。 PKA 激活剂毛喉素增强 AITC 诱导的 [Ca2+](i) 增加，卡铂本身增加细胞内环磷酸腺苷 (cAMP) 水平。此外，抑制A激酶锚定蛋白（AKAP）显着降低卡铂诱导的AITC诱导的[Ca2+](i)增强，并改善卡铂诱导的机械异常性疼痛和冷痛觉过敏。这些结果表明，卡铂通过 cAMP-PKA-AKAP 途径增加对 TRPA1 的敏感性，从而诱导机械异常性疼痛和冷痛觉过敏。
Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+](i)); however, carboplatin pretreatment enhanced the increase in [Ca2+](i) induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+](i) and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+](i) induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.