Zhang Xuming, Li Lin, McNaughton Peter A
Department of Pharmacology, University of Cambridge, Cambridge CB21PD, UK.
Neuron. 2008 Aug 14;59(3):450-61. doi: 10.1016/j.neuron.2008.05.015.
The ability of vertebrates to detect and avoid damaging extremes of temperature depends on activation of ion channels belonging to the thermo-TRP family. Injury or inflammation causes the release of inflammatory mediators which lower the threshold for detection of painful levels of heat, a process known as heat hyperalgesia. These inflammatory mediators act by at least three distinct intracellular signaling pathways. Here, we show that modulation of the sensitivity of the heat-activated ion channel TRPV1 by the protein kinases PKA and PKC and by the phosphatase calcineurin depends on the formation of a signaling complex between these enzymes, the scaffolding protein AKAP79/150 and TRPV1. We identify a critical region in the TRPV1 C-terminal which mediates binding of AKAP79/150. If binding is prevented, then sensitization by both bradykinin and PGE(2) is abrogated. AKAP79/150 is therefore a final common element in heat hyperalgesia, on which the effects of multiple proinflammatory mediators converge.
脊椎动物检测并避免极端温度伤害的能力取决于属于热TRP家族的离子通道的激活。损伤或炎症会导致炎症介质的释放，这些介质会降低对疼痛热水平的检测阈值，这一过程称为热痛觉过敏。这些炎症介质至少通过三种不同的细胞内信号通路起作用。在此，我们表明蛋白激酶PKA和PKC以及磷酸酶钙调神经磷酸酶对热激活离子通道TRPV1敏感性的调节取决于这些酶、支架蛋白AKAP79/150和TRPV1之间信号复合物的形成。我们在TRPV1 C末端鉴定出一个关键区域，该区域介导AKAP79/150的结合。如果结合被阻止，那么缓激肽和前列腺素E2（PGE2）的致敏作用都会被消除。因此，AKAP79/150是热痛觉过敏中的一个最终共同元件，多种促炎介质的作用都汇聚于此。
