PACAP-38 Induces Transcriptomic Changes in Rat Trigeminal Ganglion Cells Related to Neuroinflammation and Altered Mitochondrial Function Presumably via PAC1/VPAC2 Receptor-Independent Mechanism

• Published in: International journal of molecular sciences Vol. 23; no. 4; p. 2120
• Main Authors: Takács-Lovász, Krisztina, Kun, József, Aczél, Timea, Urbán, Péter, Gyenesei, Attila, Bölcskei, Kata, Szőke, Éva, Helyes, Zsuzsanna
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.02.2022; MDPI
• Subjects: Alternative splicing; Animal models; Animals; Annotations; Binding sites; Calcium influx; Cell culture; Cells, Cultured; Cloning; Encyclopedias; Functional analysis; Ganglia; Ganglion cells; Genes; Genomes; Glucagon; Headache; Headaches; Inflammation; intracellular calcium; Kinases; Migraine; Migraine Disorders - genetics; Migraine Disorders - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; mitochondrial electron transport chain; NADH; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - genetics; Neurons; Neuropeptides; Neuroprotection; Nicotinamide adenine dinucleotide; PAC1 protein; Pain; Peptides; Phosphorylation; Pituitary adenylate cyclase-activating polypeptide; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; pituitary adenylated cyclase-activating polypeptide (PACAP); Polypeptides; Proteins; Rats; Rats, Wistar; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - genetics; Receptors, Vasoactive Intestinal Peptide, Type II - genetics; Sensory neurons; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Transcriptome - drug effects; Transcriptome - genetics; Transcriptomics; Transient receptor potential proteins; Trigeminal ganglion; Trigeminal Ganglion - drug effects; Ubiquinone oxidoreductase; Vasoactive agents; Vasoactive intestinal peptide; transcriptomics; trigeminal ganglion; mitochondrial electron transport chain; intracellular calcium; pituitary adenylated cyclase-activating polypeptide (PACAP)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042120

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.