Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels.
Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels.
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DOI：
10.7554/elife.26280
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发表时间：
2017-08-15
期刊：
影响因子：
7.7
通讯作者：
Oberwinkler J
中科院分区：
文献类型：
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作者：
Dembla S;Behrendt M;Mohr F;Goecke C;Sondermann J;Schneider FM;Schmidt M;Stab J;Enzeroth R;Leitner MG;Nuñez-Badinez P;Schwenk J;Nürnberg B;Cohen A;Philipp SE;Greffrath W;Bünemann M;Oliver D;Zakharian E;Schmidt M;Oberwinkler J
阿片类药物是μ-阿片受体（μ OR）的激动剂，是临床上最强的止痛药。它们的行动包括一个强有力的核心部分，这也会造成严重的不利影响。然而，在伤害感受器的外周末梢上也发现了μ OR，它们在那里的激活产生了有意义的镇痛作用。外周µ OR下游的细胞机制尚未得到很好的理解。在这里，我们发现在小鼠背根神经节的神经元中，存在于伤害感受器外周部分的促伤害感受TRPM 3通道受到µOR激活的强烈抑制，比同一隔室中的其他TRP通道（如TRPV 1和TRPA 1）受到的抑制要多得多。TRPM 3通道的抑制通过涉及Gβγ蛋白的短信号级联发生，Gβγ蛋白与TRPM 3形成复合物。因此，体内外周µ OR的激活强烈减弱TRPM 3依赖性疼痛。我们的数据证实TRPM 3抑制是外周µOR激活的重要结果，表明TRPM 3拮抗剂可能是一种有用的镇痛策略。对于遭受强烈或持久疼痛的人来说，几乎没有治疗方法。目前，被称为阿片类药物的物质-包括众所周知的药物吗啡-是最强的止痛药。然而，这些药物也会引起有害的副作用，这使得它们不那么有用。像所有药物一样，阿片类药物通过与体内分子相互作用来介导其作用。在阿片类药物的情况下，这些相互作用的分子属于一组称为G蛋白偶联受体（简称GPCR）的受体蛋白。这些阿片受体广泛分布在检测和传递疼痛信号的神经细胞和大脑区域。人们对阿片受体的激活如何降低痛觉神经细胞的活性知之甚少，但有几条证据表明，一种名为TRPM 3的蛋白质可能参与其中。TRPM 3是一种通道蛋白，通过在细胞膜上形成小孔，允许钠离子和钙离子进入神经细胞，缺乏这种蛋白的小鼠对某些疼痛不太敏感。Dembla，Behrdt等人现在表明，用吗啡和类似物质激活小鼠神经细胞上的阿片受体，可以迅速减少钙离子通过TRPM 3通道的流动。进一步的实验证实，激活小鼠爪子中的阿片受体也减少了TRPM 3蛋白被激活时引起的疼痛。GPCR与一组称为G蛋白的小蛋白相互作用，当被受体激活时，G蛋白分裂成两个亚基。基于对人类肾脏细胞的研究，Dembla，Behrdt等人发现所谓的G-β-γ亚基然后将阿片受体的信号携带到TRPM 3。Quallo等人和Badheka，Yudin等人的两项独立研究也报告了类似的结果。这些新发现表明，已经用于治疗疼痛的药物可以间接地改变TRPM 3的工作方式。这些结果可能有助于科学家找到以更直接的方式降低TRPM 3活性的药物，并以更少的副作用对抗疼痛。尽管首先在人类神经细胞中证实这些新发现是很重要的。
Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy. There are very few treatments available for people suffering from strong or long-lasting pain. Currently, substances called opioids – which include the well-known drug morphine – are the strongest painkillers. However, these drugs also cause harmful side effects, which makes them less useful. Like all drugs, opioids mediate their effects by interacting with molecules in the body. In the case of opioids, these interacting molecules belong to a group of receptor proteins called G-protein coupled receptors (or GPCRs for short). These opioid receptors are widely distributed in the nerve cells and brain regions that detect and transmit pain signals. It was poorly understood how activation of opioid receptors reduces the activity of pain-sensing nerve cells, however several lines of evidence had suggested that a protein called TRPM3 might be involved. TRPM3 is a channel protein that allows sodium and calcium ions to enter into nerve cells by forming pores in cell membranes, and mice that lack this protein are less sensitive to certain kinds of pain. Dembla, Behrendt et al. now show that activating opioid receptors on nerve cells from mice, with morphine and a similar substance, rapidly reduces the flow of calcium ions through TRPM3 channels. Further experiments confirmed that activating opioid receptors in a mouse’s paw also reduced the pain caused when TRPM3 proteins are activated. GPCRs interact with a group of small proteins called G-proteins that, when activated by the receptor, split into two subunits. Based on studies with human kidney cells, Dembla, Behrendt et al. found the so-called G-beta-gamma subunit then carries the signal from the opioid receptor to TRPM3. Two independent studies by Quallo et al. and Badheka, Yudin et al. also report similar findings. These new findings show that drugs already used in the treatment of pain can indirectly alter how TRPM3 works in a dramatic way. These results might help scientists to find drugs that work in a more direct way to dial down the activity of TRPM3 and to combat pain with fewer side effects. Though first it will be important to confirm these new findings in human nerve cells.