Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Feb 20;19(1):16.
doi: 10.1186/s10194-017-0822-2.

PACAP and Its Receptors in Cranial Arteries and Mast Cells

Affiliations
Free PMC article
Review

PACAP and Its Receptors in Cranial Arteries and Mast Cells

Inger Jansen-Olesen et al. J Headache Pain. .
Free PMC article

Abstract

Background: In migraineurs pituitary adenylate cyclase activating peptide1-38 (PACAP1-38) is a potent migraine provoking substance and the accompanying long lasting flushing suggests degranulation of mast cells. Infusion of the closely related vasoactive intestinal peptide (VIP) either induces headache or flushing. This implicates the pituitary adenylate cyclase activating peptide type I receptor (PAC1) to be involved in the pathophysiology of PACAP1-38 provoked headaches. Here we review studies characterizing the effects of mainly PACAP but also of VIP on cerebral and meningeal arteries and mast cells.

Discussion: PACAP1-38, PACAP1-27 and VIP dilate cerebral and meningeal arteries from several species including man. In rat cerebral and meningeal arteries the dilation seems to be mediated preferably via vasoactive intestinal peptide receptor type 1 (VPAC1) receptors while, in human, middle meningeal artery dilation induced via vasoactive intestinal peptide receptor type 2 (VPAC2) receptors cannot be ruled out. PACAP1-38 is a strong degranulator of peritoneal and dural mast cells while PACAP1-27 and VIP only have weak effects. More detailed characterization studies suggest that mast cell degranulation is not mediated via the known receptors for PACAP1-38 but rather via a still unknown receptor coupled to phospholipase C.

Conclusion: It is suggested that PACAP1-38 might induce migraine via degranulation of dural mast cells via a yet unknown receptor.

Keywords: Cerebral artery; Mast cells; Middle meningeal artery; Migraine; PACAP; VIP.

Conflict of interest statement

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Schematic overview of selectivity of receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). Pituitary adenylate cyclase activating polypeptide receptor 1 (PAC1) has a 1000-fold greater affinity for PACAP1–27 (red) and PACAP1–38 (yellow) than for VIP (light blue). Vasoactive intestinal peptide receptor (VPAC)1 and VPAC2 bind VIP (blue) and PACAP1–27(red) and PACAP1–38 (yellow) with equal affinity. pKi (negative logarithm of the concentration that occupies half the receptor population at equilibrium) values given in the figure is adapted from [19]. No difference in receptor selectivity between PACAP1–38 and PACAP1–27 is described
Fig. 2
Fig. 2
Relaxant responses to PACAP1–27 (n = 4), VIP (n = 7) and CGRP (n = 10), expressed as % of pre-contraction induced by prostaglandin F in human cerebral arteries. Mean values ± S.E.M. are given. n = number of experiments, one from each patient. Modified from Jansen-Olesen et al. [48]
Fig. 3
Fig. 3
Low picomolar concentrations of PACAP, but not VIP, dilate isolated pressurized rat middle meningeal arteries. Cumulative concentrations of PACAP and VIP were administered to arterial segments pressurized to 40 mmHg ex vivo. Arteries were exposed to aCSF containing each concentration of PACAP1–38 or VIP for 20 min. Dilation to PACAP1–38 or VIP are expressed as percentage of maximum dilation obtained in the presence of Ca2+ −free artificial CSF containing 100 μM of the calcium channel blocker diltiazem and 1 μM of the adenylyl cyclase activator forskolin. p < 0.05 by unpaired t test, n = 4. From Syed et al. [55]
Fig. 4
Fig. 4
Effects of increasing doses (i.c.) of PACAP1–38, PACAP1–27 and VIP on middle meningeal artery diameter in the genuine closed cranial window model. Mean values ± SEM from 5 to 7 animals. Adapted from Bhatt et al. [59]
Fig. 5
Fig. 5
Toluidine blue stained intact and degranulated mast cell are shown together with a list of mast cell mediators [91]
Fig. 6
Fig. 6
Degranulation of rat peritoneal mast cells expressed as percentage of PACAP1–38, which is the strongest mast cell degranulator tested. a Shows the effect of the endogenous peptides PACAP1–38, PACAP1–27, and VIP. b Shows the effect of PACAP1–38 and the fragments PACAP6–38, PACAP16–38, and PACAP28–38. Values are given as means ± SEM of 4–8 experiments. From Baun et al. [82]
Fig. 7
Fig. 7
Degranulation of peritoneal mast cells induced by a PACAP1–38, b PACAP1–27 and c VIP in the presence of the adenylyl cyclase inhibitor SQ 22536 and the phospholipase C inhibitor U-73122 alone or in combination. Values are presented as amount of degranulation expressed as percentage of degranulation with each peptide alone. Values are given as mean ± SEM, n = 5; **p < 0.01 Mann Whitney U-test as compared to the vehicle group [82]
Fig. 8
Fig. 8
Toluidine blue staining revealed the presence of intact mast cells in dura mater from control rats (a) and the depletion of mast cells in dura mater from compound 48/80 treated rats (b)
Fig. 9
Fig. 9
Middle meningeal artery (MMA) response to 20 min i.v. infusion of CGRP (0.25 μg kg−1 min−1), PACAP1–38 (0.4 μg kg−1 min−1), PACAP1–27 (0.4 μg kg−1 min−1) and PACAP6–38 (0.4 μg kg−1 min−1). The darker color represents experiments performed on control rats while experiments represented with the lighter color are performed in mast cell depleted (MCD) rats. Mean values ± SEM are given as percentage increase in MMA diameter from the pre-stimulation baseline. Statistical analysis by ANOVA (Kruskal-Wallis test) followed by Dunn’s comparison test to compare differences from baseline values (0) ***p < 0.001; **p < 0.01; *p < 0.5. ## p < 0.01; # p < 0.05 compared to the corresponding time point in MCD rats [59]

Similar articles

See all similar articles

Cited by 9 articles

See all "Cited by" articles

References

    1. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2013;386(9995):743–800. doi: 10.1016/S0140-6736(15)60692-4. - DOI - PMC - PubMed
    1. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jonsson B. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19(1):155–162. doi: 10.1111/j.1468-1331.2011.03590.x. - DOI - PubMed
    1. Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs. 2012;26(5):375–382. doi: 10.2165/11630590-000000000-00000. - DOI - PubMed
    1. Arimura A, Somogyvári-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C. Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology. 1991;129(5):2787–2789. doi: 10.1210/endo-129-5-2787. - DOI - PubMed
    1. Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, Fujino M, et al. Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) Biochem Biophys Res Commun. 1990;170(2):643–648. doi: 10.1016/0006-291X(90)92140-U. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources

Feedback