{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:19:03Z","timestamp":1787570343984,"version":"build-2736575974"},"reference-count":24,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cephalalgia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Substance P (SP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are mast-cell-activating peptides implicated in headache and of growing therapeutic interest, but the receptors through which they act on mast cells remain poorly defined, since each peptide can signal through several receptors. Here we set out to determine which of these receptors are expressed by dural mast cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We reanalysed a pan-organ single-cell mast-cell atlas, profiling the candidate receptors for both peptides, corroborated the findings at the protein level in an independent quantitative proteomic atlas of human skin and tested them directly in a single-cell dataset of human dural mast cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In mouse connective tissue mast cells (CTMCs), Mrgprb2 was expressed in 58% of cells versus 0-0.6% for the canonical receptors. In human CTMCs, MRGPRX2 (5.9%) exceeded every canonical receptor (\u2264 0.7%). Given the known single-cell dropout of low-abundance receptor transcripts, this enrichment was confirmed at the protein level, where MRGPRX2 was mast-cell-enriched and the canonical receptors undetected. A similar pattern was found in human dural mast cells, where the canonical receptors were essentially absent (PAC\n                      <jats:sub>1<\/jats:sub>\n                      , NK2R and NK3R undetected, NK1R 0.7%) and MRGPRX2 was the only receptor detected (2.2%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Of the candidate receptors for SP and PACAP, only MRGPRX2 is expressed by CTMCs and dural mast cells at appreciable levels. MRGPRX2 is the likely route through which both peptides act on these cells and represents a potential drug target for primary headaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03331024261480167","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:05:11Z","timestamp":1787324711000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Substance P and PACAP activate dural mast cells through MRGPRX2, not NK1R or PAC\n                    <sub>1<\/sub>\n                    \/VPAC receptors"],"prefix":"10.1177","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4137-5039","authenticated-orcid":false,"given":"Lanfranco","family":"Pellesi","sequence":"first","affiliation":[{"name":"University of Southern Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Edvinsson","sequence":"additional","affiliation":[{"name":"Lund University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00034.2015"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-025-03166-y"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-025-01959-8"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-6997(25)06714-6"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.27.9.878"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-2982.1997.1703166.x"},{"key":"e_1_3_3_8_2","first-page":"174480692311813","article-title":"Roles of mast cells and their interactions with the trigeminal nerve in migraine headache","volume":"19","author":"Guan LC","unstructured":"Guan LC, Dong X, Green DP. Roles of mast cells and their interactions with the trigeminal nerve in migraine headache. Mol Pain 2023 Jan-Dec; 19: 17448069231181358.","journal-title":"Mol Pain"},{"key":"e_1_3_3_9_2","article-title":"Landscape of mast cell populations across organs in mice and humans","volume":"220","author":"Tauber M","unstructured":"Tauber M, Basso L, Martin J, et al. Landscape of mast cell populations across organs in mice and humans. J Exp Med 2023 Oct 2; 220: e20230570.","journal-title":"J Exp Med"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14022"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.012"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-39571-y"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(01)00031-0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2007.04.026"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19383-8"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.046"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/1871527320666211011110307"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.045"},{"key":"e_1_3_3_19_2","doi-asserted-by":"crossref","unstructured":"Arun N Frederick NM Tavares GA et al. A single-cell atlas of the mouse dural meninges reveals pervasive sex differences across cellular compartments. bioRxiv 2026. doi:10.64898\/2026.05.12.721894","DOI":"10.64898\/2026.05.12.721894"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-2982.2001.00161.x"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-2982.1997.1707785.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1177\/0333102420970889"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2314577"},{"key":"e_1_3_3_24_2","first-page":"333102425133613","article-title":"Effects of substance P on headache induction and arterial dilation in healthy adults","volume":"45","author":"Al-Khazali HM","unstructured":"Al-Khazali HM, Christensen RH, Gozalov E, et al. Effects of substance P on headache induction and arterial dilation in healthy adults. 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