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PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor
Infusion of pituitary adenylate cyclase activating peptide-38 (PACAP-38) provokes migraine attacks in migraineurs and headache in non-migraineurs. Adverse events like long-lasting flushing and heat sensation can be terminated with oral antihistamine treatment, indicating the involvement of mast cell...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447718/ https://www.ncbi.nlm.nih.gov/pubmed/30983973 http://dx.doi.org/10.3389/fncel.2019.00114 |
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author | Pedersen, Sara Hougaard la Cour, Sanne Hage Calloe, Kirstine Hauser, Frank Olesen, Jes Klaerke, Dan Arne Jansen-Olesen, Inger |
author_facet | Pedersen, Sara Hougaard la Cour, Sanne Hage Calloe, Kirstine Hauser, Frank Olesen, Jes Klaerke, Dan Arne Jansen-Olesen, Inger |
author_sort | Pedersen, Sara Hougaard |
collection | PubMed |
description | Infusion of pituitary adenylate cyclase activating peptide-38 (PACAP-38) provokes migraine attacks in migraineurs and headache in non-migraineurs. Adverse events like long-lasting flushing and heat sensation can be terminated with oral antihistamine treatment, indicating the involvement of mast cell activation after PACAP-infusion. Degranulation of rat peritoneal mast cells was provoked by several isoforms of PACAP via previously unknown receptor pharmacology. The effect might thus be mediated either via specific splice variants of the PAC(1)-receptor or via an unknown receptor for PACAP-38. In the present study, we characterize degranulation of rat meningeal mast cells in response to PACAP-receptor ligands. Furthermore, we investigate if PACAP-38-induced mast cell degranulation is mediated via PAC(1)-receptor splice variants and/or via the orphan Mas-related G-protein coupled member B3 (MrgB(3))-receptor. To address this, the pharmacological effect of different PACAP isoforms on meningeal mast cell degranulation was investigated in the hemisected skull model after toluidine blue staining followed by microscopic quantification. Presence of mRNA encoding PAC(1)-receptor splice variants and the MrgB(3)-receptor in rat mast cells was investigated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis. The effect of PACAP isoforms on PAC(1)- and MrgB(3)-receptor-expressing Xenopus laevis oocytes were performed by two-electrode voltage-clamp (TEVC) electrophysiology. PACAP-38 is a more potent mast cell degranulating agent than Pituitary Adenylate Cyclase Activating Peptide-27 (PACAP-27) in the meninges. Presence of mRNA encoding the PAC(1)-receptor and its different splice variants could not be detected in peritoneal mast cells by RT-PCR, whereas the orphan MrgB(3)-receptor, recently suggested to be a mediator of basic secretagogues-induced mast cell degranulation, was widely present. In PAC(1)-receptor-expressing Xenopus laevis oocytes both PACAP-38, PACAP-27 and the specific PAC(1)-receptor agonist maxadilan were equipotent, however, only PACAP-38 showed a significant degranulatory effect on mast cells. We confirmed Pituitary Adenylate Cyclase Activating Peptide(6–38) [PACAP(6–38)] to be a PAC(1)-receptor antagonist, and we demonstrated that it is a potent mast cell degranulator and have an agonistic effect on MrgB(3)-receptors expressed in oocytes. The present study provides evidence that PACAP-induced mast cell degranulation in rat is mediated through a putative new PACAP-receptor with the order of potency being: PACAP-38 = PACAP(6–38) > > PACAP-27 = maxadilan. The results suggest that the observed responses are mediated via the orphan MrgB(3)-receptor. |
format | Online Article Text |
id | pubmed-6447718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64477182019-04-12 PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor Pedersen, Sara Hougaard la Cour, Sanne Hage Calloe, Kirstine Hauser, Frank Olesen, Jes Klaerke, Dan Arne Jansen-Olesen, Inger Front Cell Neurosci Neuroscience Infusion of pituitary adenylate cyclase activating peptide-38 (PACAP-38) provokes migraine attacks in migraineurs and headache in non-migraineurs. Adverse events like long-lasting flushing and heat sensation can be terminated with oral antihistamine treatment, indicating the involvement of mast cell activation after PACAP-infusion. Degranulation of rat peritoneal mast cells was provoked by several isoforms of PACAP via previously unknown receptor pharmacology. The effect might thus be mediated either via specific splice variants of the PAC(1)-receptor or via an unknown receptor for PACAP-38. In the present study, we characterize degranulation of rat meningeal mast cells in response to PACAP-receptor ligands. Furthermore, we investigate if PACAP-38-induced mast cell degranulation is mediated via PAC(1)-receptor splice variants and/or via the orphan Mas-related G-protein coupled member B3 (MrgB(3))-receptor. To address this, the pharmacological effect of different PACAP isoforms on meningeal mast cell degranulation was investigated in the hemisected skull model after toluidine blue staining followed by microscopic quantification. Presence of mRNA encoding PAC(1)-receptor splice variants and the MrgB(3)-receptor in rat mast cells was investigated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis. The effect of PACAP isoforms on PAC(1)- and MrgB(3)-receptor-expressing Xenopus laevis oocytes were performed by two-electrode voltage-clamp (TEVC) electrophysiology. PACAP-38 is a more potent mast cell degranulating agent than Pituitary Adenylate Cyclase Activating Peptide-27 (PACAP-27) in the meninges. Presence of mRNA encoding the PAC(1)-receptor and its different splice variants could not be detected in peritoneal mast cells by RT-PCR, whereas the orphan MrgB(3)-receptor, recently suggested to be a mediator of basic secretagogues-induced mast cell degranulation, was widely present. In PAC(1)-receptor-expressing Xenopus laevis oocytes both PACAP-38, PACAP-27 and the specific PAC(1)-receptor agonist maxadilan were equipotent, however, only PACAP-38 showed a significant degranulatory effect on mast cells. We confirmed Pituitary Adenylate Cyclase Activating Peptide(6–38) [PACAP(6–38)] to be a PAC(1)-receptor antagonist, and we demonstrated that it is a potent mast cell degranulator and have an agonistic effect on MrgB(3)-receptors expressed in oocytes. The present study provides evidence that PACAP-induced mast cell degranulation in rat is mediated through a putative new PACAP-receptor with the order of potency being: PACAP-38 = PACAP(6–38) > > PACAP-27 = maxadilan. The results suggest that the observed responses are mediated via the orphan MrgB(3)-receptor. Frontiers Media S.A. 2019-03-28 /pmc/articles/PMC6447718/ /pubmed/30983973 http://dx.doi.org/10.3389/fncel.2019.00114 Text en Copyright © 2019 Pedersen, la Cour, Calloe, Hauser, Olesen, Klaerke and Jansen-Olesen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Pedersen, Sara Hougaard la Cour, Sanne Hage Calloe, Kirstine Hauser, Frank Olesen, Jes Klaerke, Dan Arne Jansen-Olesen, Inger PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title | PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title_full | PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title_fullStr | PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title_full_unstemmed | PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title_short | PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB(3)-Receptor |
title_sort | pacap-38 and pacap(6–38) degranulate rat meningeal mast cells via the orphan mrgb(3)-receptor |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447718/ https://www.ncbi.nlm.nih.gov/pubmed/30983973 http://dx.doi.org/10.3389/fncel.2019.00114 |
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