Agonistic behavior of PACAP6-38 on sensory nerve terminals and cytotrophoblast cells

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Capsaicin / pharmacology
  • Cell Line, Tumor
  • Humans
  • MAP Kinase Signaling System / physiology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Peptide Fragments / pharmacology*
  • Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology*
  • Rats
  • Rats, Wistar
  • Sensory Receptor Cells / drug effects*
  • Sensory Receptor Cells / metabolism
  • Sensory System Agents / pharmacology
  • Somatostatin / metabolism
  • Substance P / metabolism
  • Tissue Culture Techniques
  • Trachea / drug effects
  • Trachea / metabolism
  • Trophoblasts* / cytology
  • Trophoblasts* / drug effects


  • Peptide Fragments
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Sensory System Agents
  • pituitary adenylate-cyclase-activating-peptide (6-38)
  • Substance P
  • Somatostatin
  • Mitogen-Activated Protein Kinases
  • Calcitonin Gene-Related Peptide
  • Capsaicin