{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:09:18Z","timestamp":1790701758139,"version":"4.1.0"},"reference-count":67,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T00:00:00Z","timestamp":1635638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001509","name":"Royal Society Te Ap\u0101rangi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001509","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The pituitary adenylate cyclase\u2010activating peptide (PACAP) family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP\u2010responsive class B G protein\u2010coupled receptors: the PAC<jats:sub>1<\/jats:sub>, VPAC<jats:sub>1<\/jats:sub> and VPAC<jats:sub>2<\/jats:sub> receptors. The PAC<jats:sub>1<\/jats:sub> receptor may be alternatively spliced, generating variants that can differ in their pharmacological or signalling profiles. To inform drug discovery efforts targeting migraine, we need to better understand how the different PACAP\u2010responsive receptors signal and how effectively these responses can be blocked by antagonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The signalling profiles of the human PAC<jats:sub>1n<\/jats:sub>, PAC<jats:sub>1s<\/jats:sub>, VPAC<jats:sub>1<\/jats:sub> and VPAC<jats:sub>2<\/jats:sub> receptors were examined in transfected Cos7 cells for cAMP, IP<jats:sub>1<\/jats:sub>, pAkt, pERK and pCREB. Biased signalling was then quantified. The ability of antagonists to block PACAP\u201038, PACAP\u201027 or VIP stimulated cAMP accumulation at PACAP\u2010responsive receptors was also determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>PACAP\u2010responsive receptors exhibited varied pharmacological profiles but activated signalling in a similar manner. The PAC<jats:sub>1n<\/jats:sub> and PAC<jats:sub>1s<\/jats:sub> receptors displayed distinct pharmacology. At the PAC<jats:sub>1s<\/jats:sub> receptor, VIP and PHM were more potent than at the PAC<jats:sub>1n<\/jats:sub> receptor. PACAP\u2010responsive receptors displayed agonist\u2010dependent antagonism where PACAP\u201038 was less effectively antagonised compared to PACAP\u201027 and VIP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The distinct pharmacological profile displayed by the PAC<jats:sub>1s<\/jats:sub> receptor suggests that it can act as a dual receptor for VIP and PACAP. Furthermore, the effectiveness of blocking a signalling pathway can be influenced by which endogenous PACAP family agonist is present. These effects have potential implications for the development and effectiveness of drugs targeting the PACAP system.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.3\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.3\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15700","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T04:00:45Z","timestamp":1633665645000},"page":"435-453","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Characterisation of agonist signalling profiles and agonist\u2010dependent antagonism at PACAP\u2010responsive receptors: Implications for drug discovery"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-6004","authenticated-orcid":false,"given":"Zoe","family":"Tasma","sequence":"first","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0341-065X","authenticated-orcid":false,"given":"Andrew","family":"Siow","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"School of Chemical Sciences University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2579-4543","authenticated-orcid":false,"given":"Paul W. 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