Gαq/11 signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization
Gαq/11 signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization
复制标题
DOI：
10.1016/j.pain.2011.10.014
复制
发表时间：
2012-01-01
期刊：
影响因子：
7.4
通讯作者：
Kuner, Rohini
中科院分区：
文献类型：
--
作者：
Tappe-Theodor, Anke;Constantin, Cristina E.;Kuner, Rohini
外周损伤或炎症导致能够结合多种离子通道和受体的介质的释放。其中包括与G（5）、G（i/o）、G（12/13）或G（q/11）G蛋白偶联的7-跨膜受体（G蛋白偶联受体）。每一个G蛋白偶联受体通路都参与伤害性调节和疼痛处理，但体内各个信号通路的相对贡献尚未确定。G（q）/G（11）信号传导分支特别令人感兴趣，因为它导致磷脂酶C-β、蛋白激酶C的活化，从细胞内储存释放钙，并且它调节细胞外调节激酶。为了研究伤害感受器中整个G（q/11）信号通路对疼痛调节的贡献，我们使用条件性基因靶向方法在伤害感受器中选择性地产生缺乏G（q/11）的双缺陷小鼠。我们观察到伤害感受器特异性G（q）和G（11）的丢失导致爪炎症或备用神经损伤后疼痛超敏性降低。令人惊讶的是，我们的行为和电生理实验也表明G（q/11）突变小鼠的基础机械敏感性缺陷，这表明G（q/11）在急性伤害性感受的紧张性调制中具有新的功能。膜片钳记录显示，电压依赖性河豚毒素抗性和河豚毒素敏感性钠通道的伤害性感受器的G（q/11）的损失后的变化，而钾电流保持不变。我们的研究结果表明，G蛋白信号的G（q）/G（11）分支在体内伤害感受器中的功能作用不仅跨越病理性疼痛状态的致敏机制，而且在基础伤害感受和急性疼痛的紧张性调制中也起作用。(C)2011年国际疼痛研究协会。由Elsevier B出版。V.保留所有权利。
Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled receptors) coupling to G(5), G(i/o), G(12/13), or G(q/11) G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. The G(q)/G(11) signaling branch is of particular interest because it leads to the activation of phospholipase C-beta, protein kinase C, the release of calcium from intracellular stores, and it modulates extracellular regulated kinases. To investigate the contribution of the entire G(q/11)-signaling pathway in nociceptors towards regulation of pain, we generated double-deficient mice lacking G(q/11) selectively in nociceptors using a conditional gene-targeting approach. We observed that nociceptor-specific loss of G(q) and G(11) results in reduced pain hypersensitivity following paw inflammation or spared nerve injury. Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G(q/11) mutant mice, suggesting a novel function for G(q/11) in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G(q/11), whereas potassium currents remained unchanged. Our results indicate that the functional role of the G(q)/G(11) branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.