Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons.
Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons.
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DOI：
10.1523/jneurosci.6355-11.2012
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发表时间：
2012-07-11
期刊：
影响因子：
--
通讯作者：
Ma C
中科院分区：
文献类型：
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作者：
Qu L;Li Y;Pan X;Zhang P;LaMotte RH;Ma C
慢性疼痛可能伴随血清IgG免疫复合物（IgG - IC）水平升高的免疫相关疾病，但潜在机制尚不明确。我们先前证明，IgG - IC通过神经元Fc -γ受体I（FcγRI）直接兴奋背根神经节（DRG）神经元的一个亚群。这可能是将IgG - IC与疼痛和痛觉过敏联系起来的一种机制。本研究的目的是探究IgG - IC和FcγRI下游激活的信号通路和转导通道。在全细胞记录中，IgG - IC在大鼠DRG神经元中诱导了一种由Ca²⁺和Na⁺携带的非选择性阳离子电流（IIC）。通过分别降低或增加细胞内Ca²⁺缓冲能力，IIC增强或减弱，这表明该电流受细胞内钙调节。单细胞逆转录聚合酶链反应显示，瞬时受体电位经典型3（TRPC3）mRNA总是与FcγRI mRNA在同一DRG神经元中共表达。此外，钌红（一种通用的TRP通道阻滞剂）、BTP2（一种通用的TRPC通道抑制剂）或吡唑 - 3（一种选择性TRPC3阻滞剂）都能有效抑制IIC。使用小干扰RNA特异性敲低TRPC3可减弱IgG - IC诱导的Ca²⁺反应和IIC。此外，IIC可被酪氨酸激酶Syk抑制剂OXSI - 2、磷脂酶C（PLC）抑制剂新霉素，或肌醇三磷酸（IP3）受体拮抗剂2 - 氨基乙基二苯基硼酸酯或肝素阻断。这些结果表明，神经元FcγRI的激活通过Syk - PLC - IP3通路触发TRPC通道，并且TRPC3是IgG - IC对DRG神经元兴奋作用的关键分子靶点。
Chronic pain may accompany immune-related disorders with an elevated level of serum IgG immune complex (IgG-IC) but the underlying mechanisms are obscure. We previously demonstrated that IgG-IC directly excited a subpopulation of dorsal root ganglion (DRG) neurons through the neuronal Fc-gamma receptor I (FcγRI). This might be a mechanism linking IgG-IC to pain and hyperalgesia. The purpose of this study was to investigate the signaling pathways and transduction channels activated downstream of IgG-IC and FcγRI. In whole-cell recordings, IgG-IC induced a non-selective cation current (IIC) in the rat DRG neurons, carried by Ca2+ and Na+. The IIC was potentiated or attenuated by respectively lowering or increasing the intracellular Ca2+ buffering capacity, suggesting that this current was regulated by intracellular calcium. Single-cell RT-PCR revealed that transient receptor potential canonical 3 (TRPC3) mRNA was always coexpressed with FcγRI mRNA in the same DRG neuron. Moreover, ruthenium red (a general TRP channel blocker), BTP2 (a general TRPC channel inhibitor) or pyrazole-3 (a selective TRPC3 blocker), each potently inhibited the IIC. Specific knockdown of TRPC3 using small interfering RNA attenuated the IgG-IC-induced Ca2+ response and the IIC. Additionally, the IIC was blocked by the tyrosine kinase Syk inhibitor OXSI-2, the phospholipase C (PLC) inhibitor neomycin, or either the IP3 receptor antagonist 2-aminoethyldiphenylborinate or heparin. These results indicated that the activation of neuronal FcγRI triggers TRPC channels through the Syk-PLC-IP3 pathway, and that TRPC3 is a key molecular target for the excitatory effect of IgG-IC on DRG neurons.