GABA Blocks Pathological but Not Acute TRPV1 Pain Signals
GABA Blocks Pathological but Not Acute TRPV1 Pain Signals
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DOI：
10.1016/j.cell.2015.01.022
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发表时间：
2015-02-12
期刊：
影响因子：
64.5
通讯作者：
Siemens, Jan
中科院分区：
文献类型：
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作者：
Hanack, Christina;Moroni, Mirko;Siemens, Jan
辣椒素受体TRPV1的敏化是疼痛病理形式启动的核心，已知在炎症条件下，多个信号级联可增强TRPV1的活性。如何才能抵消TRPV1活动的有害升级？使用遗传蛋白质组学的方法，我们确定GABA(B1)受体亚单位在不同的炎症环境中是TRPV1敏化的真正抑制因子。我们发现内源性GABAB激动剂GABA从伤害性神经末梢释放，这表明一种自分泌反馈机制限制了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GABA(B1)受体亚基与TRPV1的紧密并列。激活GABA(B1)受体亚单位不会减弱辣椒素受体的正常功能，而是专门恢复其敏化状态。因此，利用这一机制进行止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。
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 GABA(B1) 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 GABA(B1) receptor subunit and TRPV1. Activating the GABA(B1) 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.