Sensitization to heat through G-protein-coupled receptor pathways in the isolated sciatic mouse nerve
Sensitization to heat through G-protein-coupled receptor pathways in the isolated sciatic mouse nerve
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DOI：
10.1111/j.1460-9568.2007.05582.x
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发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
Reeh, Peter W.
中科院分区：
文献类型：
--
作者：
Fischer, Michael J. M.;Reeh, Peter W.
我们先前已经证明，分离的大鼠坐骨神经轴突表达辣椒素、热和质子敏感性，并对钙依赖的降钙素基因相关肽(CGRP)释放的刺激做出反应。在无髓神经纤维的轴膜上，有刺激的囊泡胞吐和辣椒素受体，瞬时受体电位香草样物质-1(TRPV1，以前的VR1)易位的形态学证据。在感觉神经末梢，通过激活G蛋白偶联受体和相关的蛋白激酶，可以使伤害性高温下CGRP的释放变得敏感。我们提出的证据表明，在分离的小鼠坐骨神经轴突中，依赖于细胞内蛋白激酶A(PKA)和C(PKC)的转导通路也调节了热诱导(45℃)CGRP的释放。直接激活剂Forskolin和佛波酯(PMA)，以及通过G蛋白偶联受体作用的前列腺素E2(PGE(2))和缓激肽证实了这一点。抑制蛋白激酶A或C的静息状态会使热诱导的CGRP释放保持不变。在TRPV1基因敲除动物中，未观察到前列腺素E_2和缓激肽的联合刺激对热敏感。令人惊讶的是，外周神经轴突在感觉和信号转导方面的共同特性与外周感觉终末相似。
We have previously shown that isolated rat sciatic nerve axons express capsaicin, heat and proton sensitivity and respond to stimulation with a Ca++-dependent and graded calcitonin gene related peptide (CGRP) release. There is morphological evidence for stimulated vesicular exocytosis and for capsaicin receptor, transient receptor potential vanilloid type-1 (TRPV1, formerly VR1) translocation in the axolemma of unmyelinated nerve fibres. In sensory nerve terminals CGRP release in response to noxious heat can be sensitized by activation of G-protein-coupled receptors and related protein kinases. We present evidence that also in isolated mouse sciatic nerve axons the intracellular protein kinase A (PKA)- and C (PKC)-dependent transduction pathways modulate heat-induced (45 degrees C) CGRP release. This is demonstrated using the direct activators, forskolin and phorbol 12-myristate 13-acetate (PMA), as well as prostaglandin E2 (PGE(2)) and bradykinin acting through G-protein-coupled receptors. Inhibition at rest of protein kinases A or C left heat-induced CGRP release unchanged. In TRPV1 knockout animals no sensitization to heat was observed using a combined stimulation by prostaglandin E2 and bradykinin. To a surprising degree, peripheral nerve axons resemble peripheral sensory terminals in their common properties of sensory and signal transduction.