{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:58:23Z","timestamp":1792637903837,"version":"4.5.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"50","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471203"],"award-info":[{"award-number":["32471203"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371289"],"award-info":[{"award-number":["32371289"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020761","name":"High Level Innovation and Entrepreneurial Research Team Program in Jiangsu","doi-asserted-by":"publisher","award":["JSSCTD202350"],"award-info":[{"award-number":["JSSCTD202350"]}],"id":[{"id":"10.13039\/100020761","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"JST | Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20202002"],"award-info":[{"award-number":["BK20202002"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,16]]},"abstract":"<jats:p>\n                    P2X receptors, a family of ATP-activated ion channels, encompass subtypes P2X1\u20137, which are expressed in both homo- and heterotrimeric forms across various tissues. These receptors play crucial roles in pathophysiological processes such as synaptic transmission, nociception, cough, and taste perception. Extracellular ATP exists as both MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    and ATP\n                    <jats:sup>4\u2212<\/jats:sup>\n                    , with P2X3 responding to both. The evolutionary rationale for two nearly identical ligands and their distinct signaling potential remains unclear. While previous structural studies suggest a uniform ATP recognition mechanism for two endogenous ATP forms, we propose that MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    and ATP\n                    <jats:sup>4\u2212<\/jats:sup>\n                    activate P2X3 through distinct mechanisms, leading to differential physiological and pathological outcomes. Using mutagenesis, voltage-clamp fluorometry, and small molecule interventions, we identify divergent interactions of ATP\n                    <jats:sup>4\u2212<\/jats:sup>\n                    and MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    with P2X3, despite binding to the same orthosteric pocket. In\n                    <jats:italic toggle=\"yes\">\n                      P2rx3\n                      <jats:sup>D158A\/D158A<\/jats:sup>\n                    <\/jats:italic>\n                    transgenic mice, which selectively impair MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    activation, we find that MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    modulates ammonia-induced cough frequency without affecting complete Freund\u2019s adjuvant-induced inflammatory pain or sweet taste preference.\n                    <jats:italic toggle=\"yes\">\n                      P2rx3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice show deficits in all three responses. The allosteric inhibitor aurintricarboxylic acid selectively modulates ATP\n                    <jats:sup>4\u2212<\/jats:sup>\n                    and MgATP\n                    <jats:sup>2\u2212<\/jats:sup>\n                    effects, resulting in distinct antitussive and analgesic outcomes in vivo. These findings uncover a mechanism of P2X3 activation by its endogenous ligands, diverging from previous structural models and resembling the biased activation mechanisms observed in G-protein-coupled receptors, offering insights for P2X3-targeted therapeutics.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504688122","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T18:44:02Z","timestamp":1765392242000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Endogenous forms of ATP\u2013ATP\n                    <sup>4\u2212<\/sup>\n                    and MgATP\n                    <sup>2\u2212<\/sup>\n                    \u2014orchestrate distinct pathophysiological signaling via biased activation of P2X3 receptors"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8337-0434","authenticated-orcid":false,"given":"Jin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]},{"name":"Department of Chemistry, School of Science, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0084-4782","authenticated-orcid":false,"given":"Tang-Xuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jing","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Xi","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei-Bei","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Fei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4054-8543","authenticated-orcid":false,"given":"Ye","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University","place":["Nanjing, 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