Agonistic behavior of PACAP6-38 on sensory nerve terminals and cytotrophoblast cells.
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.
Reglodi
D
D
Department of Anatomy, University of Pecs, Pecs, Hungary.
Borzsei
R
R
Bagoly
T
T
Boronkai
A
A
Racz
B
B
Tamas
A
A
Kiss
P
P
Horvath
G
G
Brubel
R
R
Nemeth
J
J
Toth
G
G
Helyes
Z
Z
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D046509:Tissue Culture Techniques; D014132:Trachea / Q000187:drug effects / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects
D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018689:Sensory System Agents; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D013373:Substance P; D013004:Somatostatin; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin