Agonistic Behavior of PACAP6-38 on Sensory Nerve Terminals and Cytotrophoblast Cells
Agonistic Behavior of PACAP6-38 on Sensory Nerve Terminals and Cytotrophoblast Cells
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DOI：
10.1007/s12031-008-9089-z
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发表时间：
2008-11-01
影响因子：
3.1
通讯作者：
Helyes, Z.
中科院分区：
文献类型：
--
作者：
Reglodi, D.;Borzsei, R.;Helyes, Z.
垂体腺苷酸环化酶激活多肽 (PACAP) 的作用是通过 G 蛋白偶联受体、特定的 PAC1 受体以及 VPAC1 和 VPAC2 受体介导的，这些受体以相似的亲和力结合血管活性肠肽。基于结合亲和力研究，PACAP6-38 被发现是 PAC1 的有效拮抗剂，并已被数百项研究用作 PACAP 拮抗剂。最近，我们发现在某些细胞/组织中，PACAP6-38不会拮抗PACAP诱导的作用，但令人惊讶的是，它发挥与PACAP1-38类似的作用，表现为激动剂。在本研究中，我们报告了 PACAP6-38 对离体大鼠气管感觉神经释放神经肽的激动行为以及细胞滋养层细胞中 MAPK 信号通路的激动行为。在离体大鼠气管中，与 PACAP1-38 类似，PACAP6-38 对化学激发和辣椒素敏感传入神经的电场刺激引起的三种同时测量的感觉神经肽、P 物质、降钙素基因相关肽和生长抑素的释放产生显着的抑制作用。 PACAP6-38 对人细胞滋养层细胞中 MAPK 信号传导的影响与 PACAP1-38 相同。蛋白质印迹分析表明，两种肽形式均刺激 ERK1/2 和 JNK 磷酸化，同时抑制 p38 MAPK 磷酸化。当两种肽都存在时观察到最明显的效果。总之，我们的结果表明，PACAP6-38 在大多数细胞/组织中是 PACAP 受体拮抗剂，在其他系统中可以充当激动剂。人们对 PACAP 作用的兴趣日益浓厚，需要进一步研究该肽及其类似物的药理学特性。
The effects of pituitary adenylate cyclase activating polypeptide (PACAP) are mediated through G-protein-coupled receptors, the specific PAC1 receptor and VPAC1 and VPAC2 receptors which bind vasoactive intestinal peptide with similar affinity. Based on binding affinity studies, PACAP6-38 was discovered as a potent antagonist of PAC1 and it has been used by hundreds of studies as a PACAP antagonist. Recently, we have found that in certain cells/tissues, PACAP6-38 does not antagonize PACAP-induced effects, but surprisingly, it exerts similar actions to PACAP1-38, behaving as an agonist. In the present study, we report on the agonistic behavior of PACAP6-38 on neuropeptide release from sensory nerves of the isolated rat trachea and on the MAPK signaling pathways in cytotrophoblast cells. In isolated rat tracheae, PACAP6-38, similarly to PACAP1-38, induced significant inhibitory effects on the release of three simultaneously measured sensory neuropeptides, substance P, calcitonin gene-related peptide, and somatostatin evoked by both chemical excitation and electrical field stimulation of capsaicin-sensitive afferents. Effects of PACAP6-38 were the same as those of PACAP1-38 on MAPK signaling in human cytotrophoblast cells. Western blot analysis showed that both peptide forms stimulated ERK1/2 and JNK phosphorylation, while they both inhibited p38 MAPK phosphorylation. The most pronounced effects were observed when both peptides were present. In summary, our results show that PACAP6-38, which is a PACAP receptor antagonist in most cells/tissues, can behave as an agonist in other systems. The increasing interest in the effects of PACAP requires further studies on the pharmacological properties of the peptide and its analogues.