Paclitaxel inhibits the activity and membrane localization of PKCα and PKCβI/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons.
Paclitaxel inhibits the activity and membrane localization of PKCα and PKCβI/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons.
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DOI：
10.1016/j.mcn.2017.04.001
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Fehrenbacher JC
中科院分区：
文献类型：
--
作者：
Darby LM;Meng H;Fehrenbacher JC
周围神经病变是化疗药物紫杉醇的剂量限制性和使人衰弱的副作用。因此，阐明这种药物改变感觉神经元功能的机制对于开发成功的周围神经病变治疗方法至关重要。我们以前证明，紫杉醇长期治疗（3-5天）减少TRPV 1激动剂刺激的神经肽释放。由于TRPV 1通道的活性受到传统和新型PKC同工酶（c/nPKC）的调节，我们研究了c/nPKC是否介导紫杉醇长期治疗（300 nM; 3和5天）后神经肽释放的丧失。释放的神经肽，降钙素基因相关肽（CGRP），作为神经元敏感性的指标。紫杉醇处理后，培养的背根神经节感觉神经元用c/nPKC激活剂佛波醇12，13-二丁酸酯（PDBu）或TRPV 1激动剂辣椒素刺激，在不存在和存在常规PKCα和PKCβI/II同工酶（cPKC）的选择性抑制剂的情况下。紫杉醇（300 nM; 3天和5天）以cPKC依赖性方式减弱PDBu和辣椒素刺激的释放。在基础条件下，PKC α、βI或βII的蛋白表达、磷酸化或膜定位没有变化，但是，紫杉醇降低了cPKC活性，表现为cPKC底物磷酸化的减少。在刺激条件下，紫杉醇减弱了磷酸化PKC α、βI和βII的膜转位，为PDBu和辣椒素刺激释放的减弱提供了理论基础。我们的研究结果表明，减少cPKC活性和膜定位是负责刺激肽释放减少后，慢性治疗与紫杉醇在感觉神经元。
Peripheral neuropathy is a dose-limiting and debilitating side effect of the chemotherapeutic drug, paclitaxel. Consequently, elucidating the mechanisms by which this drug alters sensory neuronal function is essential for the development of successful therapeutics for peripheral neuropathy. We previously demonstrated that chronic treatment with paclitaxel (3–5 days) reduces neuropeptide release stimulated by agonists of TRPV1. Because the activity of TRPV1 channels is modulated by conventional and novel PKC isozymes (c/nPKC), we investigated whether c/nPKC mediate the loss of neuropeptide release following chronic treatment with paclitaxel (300 nM; 3 and 5 days). Release of the neuropeptide, calcitonin gene-related peptide (CGRP), was measured as an index of neuronal sensitivity. Following paclitaxel treatment, cultured dorsal root ganglia sensory neurons were stimulated with a c/nPKC activator, phorbol 12,13-dibutyrate (PDBu), or a TRPV1 agonist, capsaicin, in the absence and presence of selective inhibitors of conventional PKCα and PKCβI/II isozymes (cPKC). Paclitaxel (300nM; 3 days and 5 days) attenuated both PDBu- and capsaicin-stimulated release in a cPKC-dependent manner. Under basal conditions, there were no changes in the protein expression, phosphorylation or membrane localization of PKC α, βI or βII, however, paclitaxel decreased cPKC activity as indicated by a reduction in the phosphorylation of cPKC substrates. Under stimulatory conditions, paclitaxel attenuated the membrane translocation of phosphorylated PKC α, βI and βII, providing a rationale for the attenuation in PDBu- and capsaicin-stimulated release. Our findings suggest that a decrease in cPKC activity and membrane localization are responsible for the reduction in stimulated peptide release following chronic treatment with paclitaxel in sensory neurons.
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