Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Cell. 2015 Feb 12;160(4):759-770. doi: 10.1016/j.cell.2015.01.022.
Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.
辣椒素受体 TRPV1 的敏化是病理性疼痛发生的核心，并且已知多种信号级联在炎症条件下增强 TRPV1 的活性。那么，如何对抗 TRPV1 活性的有害升级呢？通过遗传蛋白质组学方法，我们发现 GABAB1 受体亚基是在各种炎症环境中 TRPV1 敏化的真正抑制剂。我们发现，内源性 GABAB 激动剂 GABA 从伤害性神经末梢释放，这表明存在一种自分泌反馈机制来限制 TRPV1 的敏化。GABAB 对 TRPV1 的作用不依赖于典型的 G 蛋白信号，而是依赖于 GABAB1 受体亚基和 TRPV1 的紧密并置。激活 GABAB1 受体亚基不会减弱辣椒素受体的正常功能，而只是使其脱敏状态得到逆转。因此，利用这种机制进行抗痛治疗可能会预防与目前可用的 TRPV1 阻滞剂相关的不良反应。
