Lee Dong Woo, Cho Pyung Sun, Lee Han Kyu, Lee Sang Hoon, Jung Sung Jun, Oh Seog Bae
Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2015 Oct 2;465(4):832-7. doi: 10.1016/j.bbrc.2015.08.096. Epub 2015 Aug 28.
TRPV1, a ligand-gated ion channel expressed in nociceptive sensory neurons is modulated by a variety of intracellular signaling pathways. Dopamine is a neurotransmitter that plays important roles in motor control, cognition, and pain modulation in the CNS, and acts via a variety of dopamine receptors (D1R-D5R), a class of GPCRs. Although nociceptive sensory neurons express D1-like receptors, very little is known about the effect of dopamine on TRPV1 in the peripheral nervous system. Therefore, in this study, we examined the effects of D1R activation on TRPV1 in mouse DRG neurons using Ca(2+) imaging and immunohistochemical analysis. The D1R agonist SKF-38393 induced reproducible Ca(2+) responses via Ca(2+) influx through TRPV1 rather than Ca(2+) mobilization from intracellular Ca(2+) stores. Immunohistochemical analysis revealed co-expression of D1R and TRPV1 in mouse DRG neurons. The PLC-specific inhibitor blocked the SKF-38393-induced Ca(2+) response, whereas the PKC, DAG lipase, AC, and PKA inhibitors had no effect on the SKF-38393-induced Ca(2+) response. Taken together, our results suggest that the SKF-38393-induced Ca(2+) response results from the direct activation of TRPV1 by a PLC/DAG-mediated membrane-delimited pathway. These results provide evidence that the trans-activation of TRPV1 following D1R activation may contribute to the modulation of pain signaling in nociceptive sensory neurons.
TRPV1是一种在伤害性感觉神经元中表达的配体门控离子通道，受多种细胞内信号通路调节。多巴胺是一种神经递质，在中枢神经系统的运动控制、认知和疼痛调节中发挥重要作用，并通过多种多巴胺受体（D1R - D5R）发挥作用，这些受体属于G蛋白偶联受体（GPCRs）。虽然伤害性感觉神经元表达D1样受体，但关于多巴胺对周围神经系统中TRPV1的影响知之甚少。因此，在本研究中，我们使用钙成像和免疫组织化学分析，研究了D1R激活对小鼠背根神经节（DRG）神经元中TRPV1的影响。D1R激动剂SKF - 38393通过TRPV1介导的钙内流诱导了可重复的钙反应，而不是从细胞内钙库动员钙。免疫组织化学分析显示，小鼠DRG神经元中D1R和TRPV1共表达。PLC特异性抑制剂阻断了SKF - 38393诱导的钙反应，而PKC、DAG脂肪酶、AC和PKA抑制剂对SKF - 38393诱导的钙反应没有影响。综上所述，我们的结果表明，SKF - 38393诱导的钙反应是由PLC / DAG介导的膜限定途径直接激活TRPV1所致。这些结果提供了证据，表明D1R激活后TRPV1的反式激活可能有助于调节伤害性感觉神经元中的疼痛信号。
