Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a broadly expressed neuropeptide which has diverse effects in both the peripheral and central nervous systems. While its neuroprotective effects have been shown in a variety of disease models, both animal and human data support the role of PACAP in migraine generation. Both PACAP and its truncated derivative PACAP(6-38) increased calcium influx in rat trigeminal ganglia (TG) primary sensory neurons in most experimental settings. PACAP(6-38), however, has been described as an antagonist for PACAP type I (known as PAC1), and Vasoactive Intestinal Polypeptide Receptor 2 (also known as VPAC2) receptors. Here, we aimed to compare the signaling pathways induced by the two peptides using transcriptomic analysis. Rat trigeminal ganglion cell cultures were incubated with 1 µM PACAP-38 or PACAP(6-38). Six hours later RNA was isolated, next-generation RNA sequencing was performed and transcriptomic changes were analyzed to identify differentially expressed genes. Functional analysis was performed for gene annotation using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. We found 200 common differentially expressed (DE) genes for these two neuropeptides. Both PACAP-38 and PACAP(6-38) treatments caused significant downregulation of NADH: ubiquinone oxidoreductase subunit B6 and upregulation of transient receptor potential cation channel, subfamily M, member 8. The common signaling pathways induced by both peptides indicate that they act on the same target, suggesting that PACAP activates trigeminal primary sensory neurons via a mechanism independent of the identified and cloned PAC1/VPAC2 receptor, either via another target structure or a different splice variant of PAC1/VPAC2 receptors. Identification of the target could help to understand key mechanisms of migraine.
Highlights
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide belonging to the vasoactive intestinal polypeptide (VIP)-secretin family, is broadly expressed throughout the body
Expression of some genes presented with a distinct pattern: Calm2, MCU were upregulated in the PACAP(6-38) and Camk2g in the PACAP-38 treated cells. These results showed the effect of PACAP-38/PACAP(6-38) on the calcium signaling pathway
This is the first description of transcriptomic changes of rat trigeminal similar after treatment with PACAP(6-38), known to be PAC1 receptor antagonist at the ganglion cells in response to PACAP-38 related to mitochondrial dysfunction and neuroinflammatory mechanisms potentially mediated by calcium signaling
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide belonging to the vasoactive intestinal polypeptide (VIP)-secretin family, is broadly expressed throughout the body. Neurogenic inflammation induced by dural sensory nerve stimulation and consequent release of proinflammatory neuropeptides such as calcitonin-gene related peptide (CGRP), tachykinins and PACAP, is an important component of migraine [21] It consists of meningeal vasodilatation, plasma protein extravasation (oedema formation) and activation of inflammatory cells including mast cells [22], which in turn release inflammatory mediators i.e., cytokines and peptides, such as PACAP [23]. These mediators further trigger the sensory nerve terminals leading to the aggravation of local neurogenic inflammation and pain [24,25]. In order to elucidate the receptorial and signaling mechanisms of PACAP-induced trigeminal ganglia primary sensory neuronal activation related to migraine, here we analyzed and compared the transcriptome changes in cell cultures treated with PACAP-38 or PACAP(6-38)
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