Stovner, L. J. et al. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17, 954–976 (2018).

Article  Google Scholar 

Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211–1259 (2017).

Article  Google Scholar 

Ashina, M. Migraine. N. Engl. J. Med. 383, 1866–1876 (2020).

Article  CAS  PubMed  Google Scholar 

Ashina, M. et al. Migraine and the trigeminovascular system — 40 years and counting. Lancet Neurol. 18, 795–804 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Ashina, M. et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 397, 1496–1504 (2021).

Article  CAS  PubMed  Google Scholar 

Al-Hassany, L. et al. Future targets for migraine treatment beyond CGRP. J. Headache Pain 24, 76 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vaudry, D. et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev. 61, 283–357 (2009).

Article  CAS  PubMed  Google Scholar 

Schytz, H. W. et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132, 16–25 (2009).

Article  PubMed  Google Scholar 

Ghanizada, H. et al. PACAP27 induces migraine-like attacks in migraine patients. Cephalalgia 40, 57–67 (2020).

Article  PubMed  Google Scholar 

Ghanizada, H. et al. Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: a 3T MRI study. Peptides 121, 170134 (2019).

Article  CAS  PubMed  Google Scholar 

Ashina, M. et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia 41, 33–44 (2021).

Article  PubMed  Google Scholar 

Ashina, M., Phul, R., Khodaie, M., Löf, E. & Florea, I. Monoclonal antibody to pituitary adenylate cyclase-activating peptide for migraine prevention. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2314577 (2024).

Harmar, A. J. et al. International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide HHS public access. Pharmacol. Rev. 50, 265–270 (1998).

CAS  PubMed  Google Scholar 

Harmar, A. J. et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br. J. Pharmacol. 166, 4–17 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tasma, Z. et al. Characterisation of agonist signalling profiles and agonist-dependent antagonism at PACAP-responsive receptors: implications for drug discovery. Br. J. Pharmacol. 179, 435–453 (2022).

Article  CAS  PubMed  Google Scholar 

Alexander, S. P. H. et al. The concise guide to pharmacology 2021/22: G protein-coupled receptors. Br. J. Pharmacol. 178, S27–S156 (2021).

CAS  PubMed  Google Scholar 

Lu, J. et al. Targeting VIP and PACAP receptor signaling: new insights into designing drugs for the PACAP subfamily of receptors. Int. J. Mol. Sci. 23, 8069 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dautzenberg, F. M., Mevenkamp, G., Wille, S. & Hauger, R. L. N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants. J. Neuroendocrinol. 11, 941–949 (1999).

Article  CAS  PubMed  Google Scholar 

Bonner, T. I. Should pharmacologists care about alternative splicing? IUPHAR review 4. Br. J. Pharmacol. 171, 1231 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kotliar, I. B., Lorenzen, E., Schwenk, J. M., Hay, D. L. & Sakmar, T. P. Elucidating the interactome of G protein-coupled receptors and receptor activity-modifying proteins. Pharmacol. Rev. 75, 1–34 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dickson, L. & Finlayson, K. VPAC and PAC receptors: from ligands to function. Pharmacol. Ther. 121, 294–316 (2009).

Article  CAS  PubMed  Google Scholar 

Foster, S. R. et al. Discovery of human signaling systems: pairing peptides to G protein-coupled receptors. Cell 179, 895–908 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Emery, A. C. & Eiden, L. E. Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor. FASEB J. 26, 3199–3211 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ravni, A. et al. A cAMP-dependent, protein kinase A-independent signaling pathway mediating neuritogenesis through Egr1 in PC12 cells. Mol. Pharmacol. 73, 1688–1708 (2008).

Article  CAS  PubMed  Google Scholar 

Stork, P. J. S. & Schmitt, J. M. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 12, 258–266 (2002).

Article  CAS  PubMed  Google Scholar 

Guo, S., Jansen-Olesen, I., Olesen, J. & Christensen, S. L. Role of PACAP in migraine: an alternative to CGRP? Neurobiol. Dis. 176, 105946 (2023).

Article  CAS  PubMed  Google Scholar 

Wootten, D., Christopoulos, A., Marti-Solano, M., Babu, M. M. & Sexton, P. M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 19, 638–653 (2018).

Article  CAS  PubMed  Google Scholar 

Yarwood, R. E. et al. Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. Proc. Natl Acad. Sci. USA 114, 12309–12314 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

De Logu, F. et al. Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice. Nat. Commun. 13, 646 (2022).

Article  PubMed  PubMed Central  Google Scholar 

May, V., Johnson, G. C., Hammack, S. E., Braas, K. M. & Parsons, R. L. PAC1 receptor internalization and endosomal MEK/ERK activation is essential for PACAP-mediated neuronal excitability. J. Mol. Neurosci. 71, 1536–1542 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Langer, I. Mechanisms involved in VPAC receptors activation and regulation: lessons from pharmacological and mutagenesis studies. Front. Endocrinol. 3, 129 (2012).

Article  CAS  Google Scholar 

Alexander, T. I. et al. Novel fluorescently labeled PACAP and VIP highlight differences between peptide internalization and receptor pharmacology. ACS Pharmacol. Transl. Sci. 6, 52–64 (2023).

Article  CAS  PubMed