Reglodi D, Borzsei R, Bagoly T, Boronkai A, Racz B, Tamas A, Kiss P, Horvath G, Brubel R, Nemeth J, Toth G, Helyes Z
Department of Anatomy, University of Pecs, Pecs, Hungary.
J Mol Neurosci. 2008 Nov;36(1-3):270-8. doi: 10.1007/s12031-008-9089-z. Epub 2008 Jul 8.
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.
垂体腺苷酸环化酶激活多肽（PACAP）的作用是通过G蛋白偶联受体介导的，即特异性的PAC1受体以及与血管活性肠肽具有相似亲和力的VPAC1和VPAC2受体。基于结合亲和力研究，PACAP6 - 38被发现是PAC1的强效拮抗剂，并且在数百项研究中被用作PACAP拮抗剂。最近，我们发现，在某些细胞/组织中，PACAP6 - 38并不拮抗PACAP诱导的效应，令人惊讶的是，它表现出与PACAP1 - 38相似的作用，充当激动剂。在本研究中，我们报告了PACAP6 - 38对离体大鼠气管感觉神经中神经肽释放以及对细胞滋养层细胞中MAPK信号通路的激动行为。在离体大鼠气管中，PACAP6 - 38与PACAP1 - 38相似，对辣椒素敏感传入神经的化学刺激和电场刺激所诱发的三种同时测量的感觉神经肽，即P物质、降钙素基因相关肽和生长抑素的释放产生显著的抑制作用。PACAP6 - 38对人细胞滋养层细胞中MAPK信号传导的作用与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，同时它们均抑制p38 MAPK磷酸化。当两种肽都存在时观察到最明显的效应。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，但在其他系统中可表现为激动剂。对PACAP效应的兴趣日益增加需要对该肽及其类似物的药理学特性进行进一步研究。
