Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA.
Mol Pain. 2011 Mar 30;7:22. doi: 10.1186/1744-8069-7-22.
The GDNF family ligands (GFLs) are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP) from isolated mouse DRG.
Inhibitors of the mitogen-activated protein kinase (MAPK) pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K) pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons.
These data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.
GDNF 家族配体（GFLs）是神经源性炎症和疼痛的调节剂。我们之前已经表明，GFLs 增加了从分离的小鼠 DRG 中释放感觉神经元神经肽降钙素基因相关肽（CGRP）。
丝裂原活化蛋白激酶（MAPK）途径的抑制剂消除了 GDNF 对 CGRP 释放的增强作用。神经营养因子诱导的 CGRP 刺激释放增强，用作感觉神经元敏化的指示，被磷脂酰肌醇-3 激酶（PI-3K）途径的抑制所消除。Ret 表达的减少消除了 GDNF 诱导的敏化，但并没有完全抑制神经营养因子或 artemin 引起的刺激诱发的 CGRP 释放增加，表明存在感觉神经元中独立于 Ret 的 GFL 诱导信号。整合素β-1 和 NCAM 参与了感觉神经元中独立于 Ret 的 GFL 信号的一部分。
这些数据表明，GFLs 诱导感觉神经元敏化的机制存在明显的差异和可变的依赖 Ret 和不依赖 Ret 的信号转导。此外，细胞内信号通路的激活与感觉神经元功能的变化之间存在明显的脱节。
