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They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. This overview emphasises the GPCRs of the nervous system, which are the research focus of the members of ERNEST COST action (CA18133) working group \u2018Biological roles of signal transduction\u2019. First, the (patho)physiological role of the nervous system GPCRs in the modulation of synapse function is discussed. We then debate the (patho)physiology and pharmacology of opioid, acetylcholine, chemokine, melatonin and adhesion GPCRs in the nervous system. Finally, we address the orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed to deorphanize them.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LINKED ARTICLES<\/jats:title>\n                    <jats:p>\n                      This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.14\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.14\/issuetoc<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16389","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:19:31Z","timestamp":1717373971000},"page":"3178-3210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ERNEST COST action overview on the (patho)physiology of GPCRs and orphan GPCRs in the nervous system"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3511-3139","authenticated-orcid":false,"given":"Necla","family":"Birg\u00fcl Iyison","sequence":"first","affiliation":[{"name":"Department of 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